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Erschienen in:

Open Access 14.08.2023

Role of the Peripheral Nervous System in Skeletal Development and Regeneration: Controversies and Clinical Implications

verfasst von: Mohamed G. Hassan, Allison L. Horenberg, Ariella Coler-Reilly, Warren L. Grayson, Erica L. Scheller

Erschienen in: Current Osteoporosis Reports | Ausgabe 5/2023

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Abstract

Purpose of Review

This review examines the diverse functional relationships that exist between the peripheral nervous system (PNS) and bone, including key advances over the past century that inform our efforts to translate these discoveries for skeletal repair.

Recent Findings

The innervation of the bone during development, homeostasis, and regeneration is highly patterned. Consistent with this, there have been nearly 100 studies over the past century that have used denervation approaches to isolate the effects of the different branches of the PNS on the bone. Overall, a common theme of balance emerges whereby an orchestration of both local and systemic neural functions must align to promote optimal skeletal repair while limiting negative consequences such as pain.

Summary

An improved understanding of the functional bidirectional pathways linking the PNS and bone has important implications for skeletal development and regeneration. Clinical advances over the next century will necessitate a rigorous identification of the mechanisms underlying these effects that is cautious not to oversimplify the in vivo condition in diverse states of health and disease.
Hinweise
Mohamed G. Hassan and Allison L. Horenberg contributed equally to this work.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Introduction

The skeleton and the peripheral nervous system (PNS) are not independent. Instead, there is a continuous bidirectional relationship across both that facilitates optimal function [1]. This can include direct, local actions of nerves on bone cells or delivery of circulating neurotransmitters through the bloodstream (Fig. 1(A), (B)). Conversely, secreted factors from skeletal cells and biomechanical signals can modulate bone-to-brain interoceptive pathways and global peripheral nerve function. Beyond this, there are many layers of possible regulation. For example, neural signals in distant organ systems such as the gut, pancreas, or liver can regulate the bone through the modulation of circulating and humoral factors [2]. PNS function can also modify the immune response. In addition, changes in peripheral nerve function can alter muscle, behavior, and movement, resulting in local adaptation of the bone due to altered biomechanical loading [3]. Though complex, these broad potential relationships between the PNS and bone present a unique opportunity for discovery. Indeed, it has become increasingly clear that an improved understanding of neural signaling pathways has important implications for skeletal development and regeneration. In this review, we will first provide an overview of the peripheral innervation of the bone during development and repair. Next, we will comprehensively summarize the outcomes from denervation experiments performed since the 1900s that inform our understanding of the in vivo relationships between the PNS and bone. Last, we will discuss the developing clinical implications and applications for PNS pathways in skeletal regeneration.

Innervation of the Bone from Development to Regeneration

Coordinated Neural Infiltration Occurs During Skeletal Development

The bone contains a widely distributed neurovascular system that includes both sensory and sympathetic nerve fibers [4•, 5, 6, 7•, 8, 9••, 10••] (Fig. 1). By contrast, the bone is not directly innervated by the motor or parasympathetic divisions of the PNS (reviewed in [11]). This well-defined pattern of skeletal innervation is established during development and is highly conserved between vertebrate species [8, 12, 13]. Axons extend from the central nervous system (CNS) to peripheral targets during gestation (day 9 to day 13 in mouse) [14]. Consistent with this, in rats, the first signs of sensory innervation of the limb skeleton have been detected in the perichondrial tissue at gestational day 15 and within the bone organ at neonatal day 4 [8, 12]. This matches the infiltration of tropomyosin receptor kinase A (TrkA) expressing sensory nerves at the primary ossification centers at gestational day 14.5 in mice primarily in response to nerve growth factor (NGF) expression by the perichondrial cells [13]. Overall, nerves and blood vessels infiltrate simultaneously in areas with high osteogenic and chondrogenic activities close to the growth plate, with sensory nerves infiltrating during gestation, approximately 10 days before the postnatal recruitment of sympathetic autonomic axons [8]. This neuronal temporal delay is synchronized with the mineralization of the primary ossification centers [8, 12]. The early presence of sensory and sympathetic nerve fibers is similarly seen during intramembranous bone development in neonatal periods [15, 16].
After development, the innervation of the mature skeleton takes on several key features. First, the highest innervation density is in the periosteum, followed by the bone marrow and cortical bone [4•, 5, 6, 7•, 9••] (Fig. 1). While sensory nerves predominate in the periosteum, this is reversed to favor sympathetic axons within the bone marrow. There is also evidence of regional variation, for example, with the thoracic vertebra having higher levels of sensory innervation than the neurocranium [7•]. Second, consistent with their vasoregulatory role, most nerves in and on the bone are closely associated with the arteriolar vascular network (> 95% in the bone/marrow; ~ 80% in periosteum) [4•, 6, 11]. In humans, this means that nerve fibers are widely distributed with arterioles throughout the Haversian canal system, and in smaller species such as rodents, nerves run with nutrient arteries through transcortical canals to enter the bone marrow. By contrast, venous sinusoids in the bone and elsewhere throughout the body are not innervated. There are also many regions of the bone and bone marrow that are relatively or completely aneural. The endosteum, for example, is essentially devoid of innervation [4•, 6]. Third, there are no nerve cell bodies or true synapses in the bone. Nerve cell bodies are located in the ganglia at the level of the spinal cord (or corresponding craniofacial ganglia) [11]. Sensory and sympathetic nerves then target the bone through unipolar axonal extensions, referred to as free nerve endings because they do not synapse with other cells. Instead, they exist locally within the environment and, depending on the nerve type, relay information to the CNS based on local changes in pressure, ions, metabolites, and/or soluble factors [11, 17, 18]. Conversely, axons in bone signal to surrounding cells through the bulk release of neurotransmitters and neuropeptides. Additional information about neuronal subtypes, targeting, and function is beyond the scope of this review but has been discussed elsewhere [11, 1720].

The Skeletal Neural Network Undergoes Active Remodeling During Bone Regeneration and Repair

Neural infiltration following skeletal injury is a well-described phenomenon that contributes to pain [2123] but may also be important for adequate healing. Secreted nerve recruitment factors termed neurotrophins are found throughout regions of bone regeneration with expression from diverse neural and non-neural cell types, including osteolineage cells, chondrocytes, macrophages, osteoclasts, and vascular cells [13, 24, 25, 26•, 27, 28]. Neurotrophins promote axonal growth into the injured site and, in some cases, may also act directly on local skeletal or endothelial cells to promote osteogenesis and angiogenesis, respectively [2830]. Expression of the neurotrophin NGF, a TrkA receptor agonist, is driven by inflammatory signals such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNFα) that rapidly upregulate its local expression, which peaks approximately 3 days after acute bone injury [26•, 27, 28]. Recent studies also convincingly demonstrate that NGF binding to neural TrkA is the main stimulus for nerve ingrowth during skeletal regeneration [24, 26•, 27]. This is consistent with the expression of TrkA on ~ 80% of sensory and ~ 100% of sympathetic nerves in the bone [5]. Expression of the TrkC agonist, neurotrophin-3 (NT-3), follows a similar pattern after fracture, while the TrkB agonist, brain-derived neurotrophic factor (BDNF), remains elevated throughout healing [28]. In distraction osteogenesis, which provides a model to explore both endochondral and intramembranous ossification, NGF and TrkA are expressed highly during the distraction phase, while BDNF, NT-3, TrkB, and TrkC are upregulated during the consolidation phase. Chemoattractants and chemorepellants also direct the projections taken by the axonal growth cones, in addition to acting locally to regulate skeletal cells. This includes galanin, netrins, semaphorins, neuropilins, and ephrins, many of which have emerging roles in bone homeostasis and repair [3134]. Many neuroregulatory factors can also directly stimulate angiogenesis, reinforcing the close coupling between nerve recruitment, vascularization, and healing [30, 35, 36].
Local nerve sprouting after injury expands the web of axons in the bone without changing the overall number of neurons in the CNS. This may have functional consequences for the interpolation of nearby signals through central relays and can also substantially modify the local release of neurotransmitters. After a fracture, sensory axons rapidly infiltrate the callus and periosteum with maximal innervation reported between days 1 and 7 after injury, prior to gradual regression during consolidation and healing [21, 27, 3740]. Infiltration of nerves occurs even prior to blood vessels in some circumstances [27, 39]. Recruitment of sympathetic nerves after injury coincides with sensory peptidergic axons, likely due to the shared expression of TrkA and response to NGF by both axon subtypes [27, 38, 41]. In angular fractures, a unique tibial fracture model with site-specific changes in bone healing, sensory and sympathetic axon density is significantly higher along the concave side of the fracture site rather than the convex side, coinciding with regions of higher bone formation [37, 38]. This suggests that early neural (and perhaps combined neurovascular) infiltration may be vital to promote adequate bone formation. By contrast, in non-healing fractures, one study in humans found a lack of innervation, while another study identified neuroma-like structures in mice [42, 43]. Persistent innervation likely contributes to sustained pain responses [21, 22, 43]. However, it is unclear whether nerves that are generally suspected to play a positive role in early regeneration may also function to inhibit healing when they persist.

Neural Contributions to Bone Homeostasis and Regeneration—Positive, Negative, Neutral, or All of the Above?

Since the 1800s, there have been nearly 100 studies that have used denervation approaches to isolate the effects of the different branches of the PNS on bone development, homeostasis, and repair (Fig. 2). These results are summarized below, and 65 key experiments across 51 manuscripts from 1900–2023 are presented in Table 1.
Table 1
Skeletal denervation studies
Study (author, year)
Model
Bone model
Denervation technique (procedure)
Bone outcome
Bone outcome summary
Targeted nerve fibers: mixed
  Xu Y et al. 2019
Mouse
Molar extraction
Surgical (unilateral inferior alveolar nerve cut)
Negative
Decreased bone formation and repair in the extraction socket. Altered immune response
  Tevlin et al. 2023
Mouse
Distraction osteogenesis
Surgical (unilateral inferior alveolar nerve cut)
Decreased bone formation on the denervated side
  Utagawa et al. 2023
Mouse
Homeostasis
Surgical (unilateral periosteal nerve scraping)
Decreased trabecular BV/TV and trabecular number and decreased bone formation rate
  Utagawa et al. 2023
Mouse
Defect
Surgical (unilateral periosteal nerve scraping)
Decreased BV/TV and regeneration on the denervated side
  Madsen et al. 1998
Rat
Fracture
Surgical (unilateral sciatic and femoral nerve cut)
Muscle atrophy after nerve cut. Increased callus size and decreased strength after denervation, even after controlling for loading with a cast
  Zhang et al. 2009
Rat
Fracture
Surgical (unilateral sciatic nerve cut)
Smaller callus size and decreased healing in the denervated group
  Gkiatas et al. 2019
Rat
Development
Surgical (unilateral brachial plexus cut)
20–30% decrease in bone strength on the denervated side at 6, 9, and 12 months of age
  Song et al. 2012
Rabbit
Distraction osteogenesis
Surgical (unilateral sciatic nerve cut)
Decreased bone formation and slower mineralization with nerve cut, even after controlling for differences in loading
  Cao et al. 2019
Rabbit
Distraction osteogenesis
Surgical (unilateral inferior alveolar nerve cut)
Lower density and formation of a new bone on the denervated side (~ − 30 to 40%)
  Al-Harby et al. 1996
Dog
Fracture
Surgical (unilateral brachial plexus cut)
Impaired callus formation and failure of radiographic union on the neurectomized side
  Tevlin et al. 2023
Human
Distraction osteogenesis
Injury (unilateral inferior alveolar nerve injury)
Lower BV/TV, cortical thickness, and bone formation on the side with the nerve injury
  Chiego and Singh 1981
Mouse
Homeostasis
Surgical (unilateral inferior alveolar nerve cut)
Negative/neutral
Slight reductions in 3H-proline uptake by osteoblasts (− 0 to 8%), no gross change in the bone
  Ma et al. 2021
Rat
Defect
Surgical (unilateral inferior alveolar nerve cut)
Decreased new bone formation on the denervated side at 1 to 4 weeks, but no change at 8 weeks post-surgery. No differences in bone mineral density at all time points
  Wu et al. 2016
Rat
Homeostasis
Surgical (unilateral inferior alveolar nerve cut)
Decreased bone mass at 2 to 4 weeks after denervation, no change at 8 weeks
  Dolan et al. 2022
Mouse
Digit tip regeneration
Surgical (unilateral digital nerve cut)
Neutral
Denervation did not impair digit tip regeneration if Dermabond was used to seal the amputated site. Denervation impaired soft tissue wound closure without Dermabond
  Aro 1985
Rat
Fracture
Surgical (unilateral sciatic nerve cut)
Positive/neutral
Callus formation and radiographic union more rapid in denervated limb with faster formation of cartilage, but no change in callus ossification
  Frymoyer and Pope 1977
Rat
Fracture
Surgical (unilateral sciatic nerve cut)
Positive
Improved fracture healing and callus strength after sciatic denervation 15–20 days following denervation and fracture
Targeted nerve fibers: sensory
  Hu et al. 2020
Mouse
Homeostasis
Chemical (30 mg/kg/day capsaicin for 1 week)
Negative
Decreased bone volume fraction and trabecular thickness in capsaicin-treated mice
  Hu et al. 2020
Defect
Chemical (30 mg/kg/day capsaicin for 1 week)
Decreased new bone formation in capsaicin-treated mice
  Hu et al. 2020
Fracture
Chemical (30 mg/kg/day capsaicin for 2 weeks)
Decreased new bone formation and fracture repair in capsaicin-treated mice
  Heffner et al. 2014
Mouse
Development
Chemical (50 mg/kg capsaicin in neonates)
Small but significant decreases in trabecular bone structure by CT, but similar bone strength and turnover
  Offley et al. 2005
Rat
Homeostasis
Chemical (25 to 50 mg/kg/day capsaicin over 2 weeks)
Decreased BMD, bone volume, and bone strength in the denervated group
  Yang et al. 2022
Rat
Homeostasis
Surgical (unilateral sensory dorsal root cut)
Cancellous bone loss and increased osteoclasts
  Ding et al. 2010
Rat
Development
Chemical (37.5, 75, or 150 mg/kg capsaicin)
Increased osteoclast markers and decreased strength at highest capsaicin dose
  Apel et al. 2009
Rat
Fracture
Chemical (1% capsaicin along the anterior and posterior aspect of the femur, local denervation)
Larger callus cross-sectional area and decreased callus strength in the denervated group
  Zhang et al. 2017
Rat
Homeostasis
Chemical (25–50 mg/kg capsaicin 3 × ; repeated every 2 weeks)
Decreased bone mass and strength
  Huang et al. 2019
Rat
Implant osseointegration
Chemical (1% capsaicin along the anterior and posterior aspect of the femur, local denervation)
Decreased trabecular bone around the implant and impaired osseointegration
  Zhang et al. 2017
Rat
Hindlimb suspension
Chemical (25–50 mg/kg capsaicin 3 × ; repeated every 2 weeks)
Negative/neutral
When controlling for loading with hindlimb suspension, sensory denervation with capsaicin did not reduce bone mass or strength
  Grey and Carr 1915
Dog
Homeostasis
Surgical (unilateral sensory dorsal root cut)
Neutral
No change in the bone by X-ray
  Eloesser 1917
Cat
Homeostasis
Surgical (unilateral sensory dorsal root cut)
Loss of reflexes, position sense, and sensation in the denervated limb. No change in the underlying strength or chemical composition of the bone, no osseous atrophy after sensory denervation. Joint disease secondary to trauma
  Jimenez-Andrade et al. 2009
Rat
Fracture
Chemical (50 mg/kg capsaicin at postnatal days 1–3)
Positive/neutral
Increased callus size and no change in time to bridging/union. Reduction in pain behavior
Targeted nerve fibers: sensory + sympathetic
  Chen et al. 2019
Mouse
Homeostasis
Chemical genetic (iDTR expression in advillin-Cre + cells + diphtheria toxin)
Negative
Bone loss, decreased osteoblasts, decreased bone formation. No change in osteoclasts
  Chen et al. 2019
Mouse
Homeostasis
Genetic (TrkA knockout in advillin-Cre + cells)
Negative/neutral
No change at 4 weeks. Decreased bone mass and formation at 12 weeks of age
  Corbin 1937
Cat
Homeostasis
Surgical (unilateral sensory dorsal root cut + / − sympathetic gangliotomy)
Neutral
No change in the denervated bones. Trauma led to articular cartilage erosion and joint disease
  Corbin 1939
Cat
Homeostasis
Surgical (unilateral sensory dorsal root cut + / − sympathetic gangliotomy)
No change in the denervated bones by X-ray, histology, or bone mass and no joint changes after limiting movement-associated trauma
Targeted nerve fibers: motor*
  Yang et al. 2022
Rat
Homeostasis
Surgical (unilateral motor ventral root cut)
Negative
Cancellous bone loss and increased osteoclasts
  Grey and Carr 1915
Rabbit
Homeostasis
Surgical (unilateral motor ventral root cut)
Bone atrophy by 2 weeks after denervation with progressive bone thinning until endpoint
Targeted nerve fibers: sympathetic
  Shi et al. 2021
Mouse
Homeostasis
Chemical (6-OHDA mediated sympathetic denervation)
Negative
Significant decreases in cortical and cancellous bone mass (− 70%) and loss of bone strength
  Shi et al. 2021
Mouse
Fracture
Chemical (6-OHDA mediated sympathetic denervation)
Impaired bone formation and callus strength
  Wagner et al. 2022
Mouse
Defect
Chemical (6-OHDA mediated sympathetic denervation)
Decreased regeneration and bone formation after 6-OHDA sympathectomy
  Scammel 1994
Rabbit
Fracture
Chemical (6-OHDA mediated sympathetic denervation)
Increased callus size but reduced callus strength in sympathectomized rabbits
  Niedermair et al. 2020
Mouse
Fracture
Chemical (6-OHDA mediated sympathetic denervation in OVX mice)
Neutral
No change in cartilage and bone formation during callus repair
  Hill et al. 1991
Rat
Homeostasis
Chemical (50 mg/kg/day guanethidine for 3 weeks, 1 week after birth)
No change in bone mass or bone formation rate in the tibia, but increased osteoclast recruitment after extraction
  Kizilay et al. 2020
Rat
Fracture
Surgical (unilateral stellate sympathetic gangliotomy)
No difference in bone formation, union, and remodeling between groups
  Harris and Mcdonald 1936
Kitten
Development
Surgical (unilateral lumbar sympathetic gangliotomy)
No change in bone growth or length after sympathectomy
  Key and Moore 1933
Cat
Fracture & defect
Surgical (unilateral thoracic sympathetic gangliotomy)
No difference in fracture or defect healing between the sympathectomized or intact sides
  Corbin 1939
Cat
Homeostasis
Surgical (unilateral or bilateral lumbar sympathetic gangliotomy)
No change in the bone by X-ray, histology, or bone mass
  Harris and Mcdonald 1936
Puppy
Development
Surgical (unilateral lumbar sympathetic gangliotomy)
No change in bone growth or length after sympathectomy
  Pearse and Morton 1930
Dog
Fracture
Surgical (unilateral lumbar sympathetic gangliotomy)
Little difference in healing with sympathectomy
  Harris and Mcdonald 1936
Lamb
Development
Surgical (unilateral lumbar sympathetic gangliotomy)
No change in bone growth or length after sympathectomy
  Guan et al. 2023
Rat
Homeostasis
Chemical (guanethidine-mediated sympathetic denervation)
Negative/neutral
No change in the bone in the spine, decreased trabecular BMD, BV/TV, and Tb.Th. in the tibia (~ − 30%)
  Cherruau et al. 1999
Rat
Molar extraction
Chemical (40 mg/kg/day guanethidine for 21 days)
Positive
Decreased bone resorption surface and osteoclast formation
  Wang 2012
Rat
Distraction osteogenesis
Surgical (unilateral cervical sympathetic gangliotomy)
Increased bone formation at 1 (+ 45%) and 14 days (+ 13%) of consolidation
  Du et al. 2014
Rat
Distraction osteogenesis
Surgical (unilateral cervical sympathetic gangliotomy)
Improved bone marrow mesenchymal stem cell migration into the defect
  Palma 1925, as reported in Colp 1933
Rabbit
Fracture
Surgical (unilateral cervical sympathetic gangliotomy)
Improved early vascularization and fracture healing on the sympathectomized side
  Uffreduzzi 1924, as reported in Colp 1933
Rabbit
Fracture
Surgical (unilateral periarterial sympathectomy)**
Improved early vascularization and fracture healing on the sympathectomized side
  Ito and Asami 1932
Dog
Fracture
Surgical (unilateral lumbar sympathetic gangliotomy)
Increased healing with lumbar sympathectomy (11/12)
  Zollinger 1933
Dog
Fracture
Surgical (unilateral lumbar sympathetic gangliotomy)
Greater regeneration of the sympathectomized side in 15/17 cases but considered “slight” and not to warrant clinical application
  Ito and Asami 1932
Dog
Fracture
Surgical (unilateral periarterial sympathectomy)**
Increased healing with periarterial sympathectomy (11/13)
  Fontaine 1926, as reported in Colp 1933
Dog
Fracture
Surgical (unilateral periarterial sympathectomy)**
Improved callus strength and healing on the sympathectomized size
  Colp 1933
Dog
Fracture
Surgical (unilateral periarterial sympathectomy)**
Improved vascularization and fracture healing on the sympathectomized size
  Harris and Mcdonald 1936
Human
Development
Surgical (unilateral lumbar sympathetic gangliotomy)
Positive (acceleration or maintenance of the rate of growth of the child’s leg on the sympathectomized side in 63% of cases, no improvement in 37%)
*Motor nerves do not innervate the bone directly but can influence the surrounding muscle. **Periarterial sympathectomy denervates the adventitia of the main vascular branch to the bone but may not denervate the bone itself

Mixed Denervation Approaches Reinforce the Link Between the Muscle and Bone and Provide New Clues About Neural Coordination of Soft and Hard Tissue Healing

Sir D’Arcy Thompson in 1917 said, “Between muscle and bone there can be no change in the one but it is correlated with changes in the other” [44]. The same remains true within the context of the neural regulation of the bone. Specifically, any reduction of the motor innervation of muscle will subsequently lead to progressive skeletal atrophy due to loss of muscle mass. This is most clearly shown after the transection of the ventral motor roots of the spinal cord to induce selective motor denervation of the limb [45, 46•] and has since been repeated many times in studies of peripheral nerve resection. This most commonly includes the brachial plexus (upper limb), sciatic and femoral nerves (lower limb), and inferior alveolar nerve (mandible) that contain mixed populations of motor, sensory, and sympathetic axons [4759]. In 12/14 studies in Table 1, when mixed surgical denervation was paired with models of bone injury, denervation had a negative impact on soft tissue closure, fracture repair, or osseous defect healing.
Mixed peripheral nerve function has also been studied within the context of axolotl limb regeneration. Axolotls are capable of full limb re-growth when amputation is performed proximal to the elbow joint. Local expression of neuregulin-1 and its receptor, ErbB2, are decreased with limb denervation [60]. In addition, denervation delays regeneration, while supplementation of neuregulin-1 rescues regeneration in denervated limbs. The closest analog to this in mammals is the regeneration of the terminal portion of the digit tip. Sensory and sympathetic nerves are found in the digit tip prior to and during regeneration [61••]. However, despite work suggesting that nerves are required for complete renewal [62], a recent study found that nerves are exclusively required for soft tissue wound closure rather than bone regeneration. Thus, when open wounds were treated with Dermabond to stimulate closure, regenerated digits with denervation were morphologically similar to controls [63]. Overall, mixed denervation approaches demonstrate that an intact PNS supports optimal regeneration when present. In addition to maintaining muscle mass, this work also hints at mechanisms that may include the neural regulation of both hard and soft tissue healing.

Studies of Surgical, but Not Chemical, Denervation Show that Depletion of Sympathetic Nerves May Promote Bone Accrual and Repair by Increasing Blood Flow

In the early 1900s, an extensive series of experiments were undertaken to understand the impact of surgical sympathetic denervation on bone development and fracture healing (Fig. 2, Table 1). The rationale was the finding that sympathetic denervation could promote local vascularization and blood flow. The first surgical method consisted of the removal of the sympathetic ganglia (e.g., unilateral lumbar gangliotomy to denervate the lower limb). This results in permanent and selective removal of the sympathetic nerves in a small body region. Fracture or bone defect healing with sympathetic gangliotomy showed either no change [6468] or increased healing on the sympathectomized side [67, 6971]. Unilateral lumbar sympathectomy was also performed in 46 children with leg paralysis and unilateral shortening due to poliomyelitis, to increase the growth of the affected limb [72]. Despite failed experiments in kittens, puppies, and lambs that showed no difference in limb growth, there was an acceleration or maintenance of the rate of growth of the paralyzed leg on the sympathectomized side in 63% of cases. The second approach, termed periarterial sympathectomy, consisted of the removal of the sympathetic nerve axon-containing adventitia from the vessel wall (e.g., the femoral artery for the lower limb). This causes sympathetic denervation of the vessel itself and any downstream site that was originally targeted by this vascular network. Overall, periarterial sympathectomy resulted in increased blood flow with more rapid callus formation, ossification, and healing on the sympathectomized side in dogs, rabbits, and humans [71, 73, 74]. However, despite some apparent clinical success, these procedures received substantial pushback from other members of the medical community that did not find them to be advantageous, and surgical sympathectomy has since been discontinued for growth- or fracture-related outcomes.
In contrast to the generally positive results of surgical sympathectomy, chemical sympathectomy often leads to bone loss, impaired bone strength, and impaired bone healing (Fig. 2, Table 1) [7581]. The discrepancy between the surgical and chemical denervation models may be due to the whole-body suppression of sympathetic adrenergic systems by chemical treatment, resulting in substantial global alterations in mouse health that are not present after regional surgical denervation.

Sensory Nerves are Required to Ensure Optimal Skeletal Loading and May Augment Bone Formation and Repair in Settings of Development and Injury

Surgical studies have also been performed to selectively disrupt the sensory innervation of the bone (Table 1). Interpretation is challenging because sensory denervation causes improper limb use and joint trauma due to altered position sense. However, when isolated from changes in biomechanics and loading, surgical sensory denervation generally does not alter bone mass or strength over long periods of time (up to 3 years in one study) [45, 46•, 66, 8284]. In the 1930s, this led to the conclusion that skeletal sensory innervation is not necessary for the maintenance of bone. However, more recently, sensory nerves have gained renewed attention based on their extensive pattern of infiltration following bone injury. Though some studies have shown neutral effects, chemical and genetic denervation studies have generally found that local sensory denervation during bone healing impairs implant osseointegration, alters fracture callus size, and decreases bone repair [23, 8587]. Whole-body chemical and genetic methods of sensory denervation also lead to generalized bone loss in the absence of injury [85, 8891]. As with chemical sympathetic denervation, differences between surgical and genetic/chemical approaches may be due to the impact of global sensory denervation on peripheral systems (sight, smell, gait, etc.), in addition to any local effects. In addition, any benefits of sensory nerve recruitment for fracture repair must be balanced with clinical needs. Management of fractures is challenging, particularly in patients with multiple co-morbidities, limited mobility, and pain. Currently, local sensory neurolysis is a clinically approved adjunct to manage pain for inoperable hip fractures [92•, 93]. Neurolysis substantially improves mobility and quality of life, which can also independently promote positive clinical outcomes for these patients.

Clinical Adaptation of Peripheral Neural Pathways for Skeletal Regeneration

The PNS mediates a multitude of critical functions throughout the body, and denervation studies over the last century show that gross modification to the PNS is generally not warranted to promote bone repair. However, the isolation of novel molecular mechanisms linking the PNS and bone has also led to the identification of several high-yield pathways that inform targeted strategies to support skeletal regeneration.

Methods to Enhance Nerve Infiltration Are Associated with Increased Bone Healing

With sensory denervation often resulting in impaired bone healing after injury (Table 1), therapeutic studies have aimed to promote neural ingrowth and, by proxy, encourage bone formation. Nerves and vessels infiltrate within the first week following a fracture. Thus, therapeutic methods aim to improve neurovascular infiltration early in the healing process. One study utilized MMP-degradable tissue-engineered periosteum (MMP-TEP)-coated allografts to improve scaffold integration with the native tissue since periosteum can help direct neurovascular infiltration [94]. The MMP-TEP allograft group demonstrated early-stage neurovascularization and improved both mineralization and mechanical properties of femoral defects as compared to hydrogel-TEP allografts and allografts alone. An additional group of studies has aimed to encourage bone formation by redirecting the entire nerve bundles to the injury region to improve neural infiltration and neuropeptide release during healing. Positioning the cut end of the peripheral nerve trunk into tissue-engineered bone grafts (TEBGs) improved callus and bone formation compared to TEBG-only samples [9598]. In addition, nerve bundle TEBGs increased the expression of neuropeptides and their receptors and improved vascularization in the defect region. The mechanisms involved in this model were not explored in depth; however, the implanted nerve bundles may either be supporting innervation/neuropeptide production or perhaps serving as a reservoir of pro-regenerative signals from nerve-associated cells.

Sensory Neurotransmitter Calcitonin Gene–Related Peptide (CGRP) Can Enhance Bone Repair

One possible osteoanabolic factor is the sensory neurotransmitter CGRP. In addition to being a potent vasodilator, in vivo and in vitro studies report that CGRP promotes osteoblast differentiation and inhibits bone resorption [99]. CGRP receptor deletion in osteoprogenitors during fracture healing decreases callus and cartilage area as well as cell proliferation, resulting in an overall impairment to fracture healing [100]. Conversely, methods that increase the concentration of CGRP within skeletal defects can enhance the rate of bone formation and repair [99, 101]. For example, atypical femoral fractures, which exhibit delayed healing and can occur following bisphosphonate treatment, demonstrate lower CGRP expression, reduced bony bridging, and increased fibrous tissue formation. Local injection of CGRP (100 nM) for 14 days after injury helped to restore healing in these fractures [102••].
While exogenous neuropeptide delivery can enhance regeneration, high levels are often required. To avoid this, other therapeutic approaches aim to stimulate endogenous release by exploiting materials or systems that encourage neuronal signaling or neuropeptide expression. For example, biomaterials containing divalent metal cations such as magnesium induce local CGRP release and stimulate robust periosteum-derived stem cell osteogenic differentiation [102••, 103, 104••]. Direct stimulation of sensory nerve cell bodies in the dorsal root ganglia with an implanted microelectrical stimulation system (IMESS) also enhances CGRP production and drives spinal fusion only in IMESS-targeted areas. Similarly, in osteoporotic femoral fracture healing, IMESS at the dorsal root ganglia (20 min/day for 2 weeks) improves vascularization and fracture healing in a CGRP-dependent manner without increasing pain-like responses [105••]. Conversely, the intraperitoneal injection of CGRP inhibitors in rats negatively affected fracture healing, demonstrating a significant decrease in the formation of the mineralized callus [106]. Balancing the osteoanabolic effects of sensory neurotransmitters such as CGRP with pain outcomes is crucial since these factors can also enhance nociception [107]. Adding to the complexity, CGRP inhibitors such as atogepant and erenumab are used clinically for the treatment of migraine [108]. Development of pro-regenerative paradigms will require careful consideration of current therapeutics and the actions of target neurotransmitters across systems.

Schwann Cell–Secreted Factors Signal Bone-Forming Cells to Activate Repair Responses

Peripheral nerve axons are wrapped by a protective sheath of myelinating or non-myelinating Schwann cells. After an injury, certain populations of Schwann cells can disassociate from damaged axons to expand at the site of injury. Schwann cells primarily modulate bone regeneration through secreted factors that signal bone-forming cells. In mouse digit tip regeneration, denervation inhibited Schwann cell infiltration, depleting Schwann cell–secreted factors, including OSM and PDGF-AA, and inhibiting regeneration [109]. Transplantation of additional Schwann cells or local injection of OSM and PDGF-AA was able to rescue the impaired healing [109]. Schwann cell–derived exosomes were also shown to enhance osteogenic differentiation in vitro and improve bone formation in vivo when included in a titanium alloy scaffold [110]. Similarly, when Schwann cells were included in scaffolds along with osteoblasts and endothelial cells, angiogenesis and vascularization were enhanced in vivo [111]. Mechanistically, in vitro studies suggest that Schwann cell–derived factors increase the proliferation of skeletal stem cells and endothelial cells while signaling through the VEGF, ERK/MAPK, and PI3k-Akt pathways [112].

β-Blockers Increase BMD, Reduce Fracture Risk, and Promote Healing

Surgical denervation studies pinpoint the sympathetic nervous system as a negative regulator of bone (Fig. 2, Table 1). Consistent with this, norepinephrine, the primary neurotransmitter of sympathetic adrenergic axons, can act on skeletal β-adrenergic receptors to suppress bone formation and increase osteoclast function, leading to decreased bone mass [113115]. This informs studies on the effects of β-blockers, a group of common antihypertensive medications, on bone homeostasis and repair. β-blockers inhibit the diverse effects of the neural- and adrenal-derived catecholamines, including norepinephrine. Clinical use of β-blockers is associated with reduced risk of fracture and increased bone mineral density [116118]. Treatment with β-blockers in mouse models increases bone mass due to enhanced bone formation and decreased bone resorption [114]. The β-blocker propranolol can also promote mineral apposition, callus formation, and strength in rodent femoral defects [119]. Though it is unclear if the benefits to the bone are due to direct actions on bone cells (vs. vasoregulatory or other effects), β-blockers remain a promising therapeutic strategy for managing osteoporosis and enhancing bone healing. In addition, recent studies have identified alternate pathways that converge on the regulation of sympathetic tone to modulate bone mass. For example, genetic downregulation of PGE2 signaling by advillin-expressing sympathetic and sensory nerves or introducing divalent cations such as magnesium can suppress sympathetic activity, promoting osteoblast formation and increases in the bone [85, 91, 104••, 120]. Increased sympathetic tone has also been proposed as a putative mechanism underlying bone loss and fragility in diseases including chronic heart failure [78] and impaired fracture repair with the use of medications such as SSRIs [121], providing targeted opportunities for future intervention.

Activation of NGF/TrkA Signaling Can Augment Bone Healing but Needs to be Balanced with Pain and Tumor-Promoting Responses

Therapeutic approaches using growth factors are popular for targeting known regeneration pathways, as they involve simple strategies to stimulate the host microenvironment. Consistent with this, local application of the neurotrophin NGF activates neuronal signaling, vascularization, and other bone resident cells that stimulate bone formation [30, 41, 122126]. Genetic targeting approaches have shown that the bone anabolic effects are largely mediated by the activation of TrkA, the high-affinity receptor of NGF [26•, 27], with the potential for additional pro-regenerative actions of the low-affinity NGF receptor p75-NTR [127]. Specifically, when paired with rodent models of long bone fracture or calvarial defect, global inhibition of TrkA signaling reduces vascularization, osteoblastic activity, and ossification rate [26•, 27]. Conversely, treatment with synthetic TrkA agonist gambogic amide can promote angiogenesis and bone repair [128]. The mechanism underlying this effect remains to be clarified and may involve the activation of TrkA on neural, vascular, and/or local skeletal cells [30, 128]. Beyond this, targeted inhibition of p75-NTR in osteoblast precursors can restrict osteoprogenitor migration into the repair site [127]. Other nerve regulatory factors and neuropeptides such as BDNF, substance P, Sema3A, vasoactive intestinal peptide, and galanin have also been used to trigger bone healing and demonstrated similar results [70, 129136].
NGF/TrkA signaling is also a major regulator of peripheral pain. Given this, clinical anti-NGF therapies to treat musculoskeletal pain are currently under development, and inhibition of NGF/TrkA signaling to treat fracture pain has been tested in rodents. In this case, anti-NGF and anti-TrkA antibodies successfully reduced pain behaviors without affecting fracture repair [137, 138]. In addition, NGF may also be relevant to tumorigenesis [139]. Many studies highlight the increase of NGF secretion and its receptors in the microenvironment of different cancer types [140]. For this reason, increasing attention is directed toward NGF and/or TrkA as a therapeutic target for effectively controlling tumor progression. Most recently, this includes the clinical use of an emerging class of TRK inhibitors to treat TRK fusion–positive cancers [141]. While TRK inhibitors have favorable overall safety, off-target adverse events, including weight gain, dizziness/ataxia, paraesthesias, and bone fracture, are occasionally observed [141, 142]. Future studies will be essential to understand the impact of the clinical modulation of TRK signaling on the bone microenvironment during the maintenance and healing phases.

Conclusions

Studies on the relationships between the PNS and bone initially peaked in the early 1900s. Over 100 years later, we have now uncovered diverse links between the PNS and the skeleton that occur during bone homeostasis, development, and repair. Overall, a common theme of balance emerges whereby an orchestration of both local and systemic neural functions must align to promote optimal repair while limiting negative consequences such as pain. Advances over the next century will necessitate a rigorous identification of the mechanisms underlying these effects that is cautious not to oversimplify the in vivo condition. Clinical use of sensory neurolysis, CGRP inhibitors, and TRK-targeting therapies will undoubtedly inform our understanding of their necessity for bone health and the potential to leverage the anabolic components of these pathways to promote regeneration. In addition, β-blockers and PNS-targeting bioactive implant materials represent emerging strategies to support repair.

Declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Competing Interests

The authors declare no competing interests.
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Literatur
1.
Zurück zum Zitat Wan Q-Q, Qin W-P, Ma Y-X, Shen M-J, Li J, Zhang Z-B, et al. Crosstalk between bone and nerves within bone. Adv Sci (Weinh). 2021;8:2003390.PubMedCrossRef Wan Q-Q, Qin W-P, Ma Y-X, Shen M-J, Li J, Zhang Z-B, et al. Crosstalk between bone and nerves within bone. Adv Sci (Weinh). 2021;8:2003390.PubMedCrossRef
3.
4.
Zurück zum Zitat • Lorenz MR, Brazill JM, Beeve AT, Shen I, Scheller EL. A neuroskeletal atlas: spatial mapping and contextualization of axon subtypes innervating the long bones of C3H and B6 mice. J Bone Miner Res. 2021;36:1012–25. This paper maps the sensory and sympathetic innervation of mouse long bone and provides full thickness reference atlases that relate patterns of innervation to the surrounding muscle. Three unique neuroskeletal niches within the periosteum are also defined.PubMedCrossRef • Lorenz MR, Brazill JM, Beeve AT, Shen I, Scheller EL. A neuroskeletal atlas: spatial mapping and contextualization of axon subtypes innervating the long bones of C3H and B6 mice. J Bone Miner Res. 2021;36:1012–25. This paper maps the sensory and sympathetic innervation of mouse long bone and provides full thickness reference atlases that relate patterns of innervation to the surrounding muscle. Three unique neuroskeletal niches within the periosteum are also defined.PubMedCrossRef
5.
Zurück zum Zitat Castañeda-Corral G, Jimenez-Andrade JM, Bloom AP, Taylor RN, Mantyh WG, Kaczmarska MJ, et al. The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A. Neuroscience. 2011;178:196–207.PubMedCrossRef Castañeda-Corral G, Jimenez-Andrade JM, Bloom AP, Taylor RN, Mantyh WG, Kaczmarska MJ, et al. The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A. Neuroscience. 2011;178:196–207.PubMedCrossRef
6.
Zurück zum Zitat Sayilekshmy M, Hansen RB, Delaissé J-M, Rolighed L, Andersen TL, Heegaard A-M. Innervation is higher above bone remodeling surfaces and in cortical pores in human bone: lessons from patients with primary hyperparathyroidism. Sci Rep. 2019;9:5361.PubMedPubMedCentralCrossRef Sayilekshmy M, Hansen RB, Delaissé J-M, Rolighed L, Andersen TL, Heegaard A-M. Innervation is higher above bone remodeling surfaces and in cortical pores in human bone: lessons from patients with primary hyperparathyroidism. Sci Rep. 2019;9:5361.PubMedPubMedCentralCrossRef
7.
Zurück zum Zitat • Steverink JG, Oostinga D, van Tol FR, van Rijen MHP, Mackaaij C, Verlinde-Schellekens SAMW, et al. Sensory innervation of human bone: an immunohistochemical study to further understand bone pain. J Pain. 2021;22:1385–95. The authors aimed to quantify sensory nerve fiber density in different anatomical locations of human bones using immunohistochemistry and confocal microscopy. They reported that the distribution of the sensory nerve fibers varied across different bone locations; however, there was no difference across genders. • Steverink JG, Oostinga D, van Tol FR, van Rijen MHP, Mackaaij C, Verlinde-Schellekens SAMW, et al. Sensory innervation of human bone: an immunohistochemical study to further understand bone pain. J Pain. 2021;22:1385–95. The authors aimed to quantify sensory nerve fiber density in different anatomical locations of human bones using immunohistochemistry and confocal microscopy. They reported that the distribution of the sensory nerve fibers varied across different bone locations; however, there was no difference across genders.
8.
Zurück zum Zitat Sisask G, Silfverswärd CJ, Bjurholm A, Nilsson O. Ontogeny of sensory and autonomic nerves in the developing mouse skeleton. Auton Neurosci. 2013;177:237–43.PubMedCrossRef Sisask G, Silfverswärd CJ, Bjurholm A, Nilsson O. Ontogeny of sensory and autonomic nerves in the developing mouse skeleton. Auton Neurosci. 2013;177:237–43.PubMedCrossRef
9.
Zurück zum Zitat •• Thai J, Kyloh M, Travis L, Spencer NJ, Ivanusic JJ. Identifying spinal afferent (sensory) nerve endings that innervate the marrow cavity and periosteum using anterograde tracing. J Comp Neurol. 2020;528:1903–16. This paper uses a unique approach to trace nerves from the dorsal root ganglia to the bone. This provides an unbiased identification of sensory nerve subtypes in skeletal tissues and shows that the unique TH+ sensory afferent population is not present in bone.PubMedCrossRef •• Thai J, Kyloh M, Travis L, Spencer NJ, Ivanusic JJ. Identifying spinal afferent (sensory) nerve endings that innervate the marrow cavity and periosteum using anterograde tracing. J Comp Neurol. 2020;528:1903–16. This paper uses a unique approach to trace nerves from the dorsal root ganglia to the bone. This provides an unbiased identification of sensory nerve subtypes in skeletal tissues and shows that the unique TH+ sensory afferent population is not present in bone.PubMedCrossRef
10.
Zurück zum Zitat •• Utagawa K, Shin T, Yamada H, Ochi H, Sunamura S, Unno A, et al. Three-dimensional visualization of neural networks inside bone by Osteo-DISCO protocol and alteration of bone remodeling by surgical nerve ablation. Sci Rep. 2023;13:4674. This paperuses tissue clearing techniques to provide a beautiful view of the relatively sparse neural network in the whole bone marrow, which is otherwise difficult to appreciate using sectioning-based techniques. It also explores the role of ultra-local surgical denervation on bone homeostasis.PubMedPubMedCentralCrossRef •• Utagawa K, Shin T, Yamada H, Ochi H, Sunamura S, Unno A, et al. Three-dimensional visualization of neural networks inside bone by Osteo-DISCO protocol and alteration of bone remodeling by surgical nerve ablation. Sci Rep. 2023;13:4674. This paperuses tissue clearing techniques to provide a beautiful view of the relatively sparse neural network in the whole bone marrow, which is otherwise difficult to appreciate using sectioning-based techniques. It also explores the role of ultra-local surgical denervation on bone homeostasis.PubMedPubMedCentralCrossRef
11.
Zurück zum Zitat Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL. Nerves in bone: evolving concepts in pain and anabolism. J Bone Miner Res. 2019;34:1393–406.PubMedCrossRef Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL. Nerves in bone: evolving concepts in pain and anabolism. J Bone Miner Res. 2019;34:1393–406.PubMedCrossRef
12.
Zurück zum Zitat Sisask G, Bjurholm A, Ahmed M, Kreicbergs A. Ontogeny of sensory nerves in the developing skeleton. Anat Rec. 1995;243:234–40.PubMedCrossRef Sisask G, Bjurholm A, Ahmed M, Kreicbergs A. Ontogeny of sensory nerves in the developing skeleton. Anat Rec. 1995;243:234–40.PubMedCrossRef
13.
Zurück zum Zitat Tomlinson RE, Li Z, Zhang Q, Goh BC, Li Z, Thorek DLJ, et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep. 2016;16:2723–35.PubMedPubMedCentralCrossRef Tomlinson RE, Li Z, Zhang Q, Goh BC, Li Z, Thorek DLJ, et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep. 2016;16:2723–35.PubMedPubMedCentralCrossRef
14.
Zurück zum Zitat Wang L, Mongera A, Bonanomi D, Cyganek L, Pfaff SL, Nüsslein-Volhard C, et al. A conserved axon type hierarchy governing peripheral nerve assembly. Development. 2014;141:1875–83.PubMedCrossRef Wang L, Mongera A, Bonanomi D, Cyganek L, Pfaff SL, Nüsslein-Volhard C, et al. A conserved axon type hierarchy governing peripheral nerve assembly. Development. 2014;141:1875–83.PubMedCrossRef
15.
Zurück zum Zitat Kosaras B, Jakubowski M, Kainz V, Burstein R. Sensory innervation of the calvarial bones of the mouse. J Comp Neurol. 2009;515:331–48.PubMedPubMedCentral Kosaras B, Jakubowski M, Kainz V, Burstein R. Sensory innervation of the calvarial bones of the mouse. J Comp Neurol. 2009;515:331–48.PubMedPubMedCentral
16.
Zurück zum Zitat Alberius P, Skagerberg G. Adrenergic innervation of the calvarium of the neonatal rat. Its relationship to the sagittal suture and developing parietal bones. Anat Embryol. 1990;182:493–8.CrossRef Alberius P, Skagerberg G. Adrenergic innervation of the calvarium of the neonatal rat. Its relationship to the sagittal suture and developing parietal bones. Anat Embryol. 1990;182:493–8.CrossRef
18.
Zurück zum Zitat Mantyh PW. Mechanisms that drive bone pain across the lifespan. Br J Clin Pharmacol. 2019;85:1103–13.PubMedCrossRef Mantyh PW. Mechanisms that drive bone pain across the lifespan. Br J Clin Pharmacol. 2019;85:1103–13.PubMedCrossRef
19.
Zurück zum Zitat Zeisel A, Hochgerner H, Lönnerberg P, Johnsson A, Memic F, van der Zwan J, et al. Molecular architecture of the mouse nervous system. Cell. 2018;174:999-1014.e22.PubMedPubMedCentralCrossRef Zeisel A, Hochgerner H, Lönnerberg P, Johnsson A, Memic F, van der Zwan J, et al. Molecular architecture of the mouse nervous system. Cell. 2018;174:999-1014.e22.PubMedPubMedCentralCrossRef
20.
Zurück zum Zitat Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou D, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 2015;18:145–53.PubMedCrossRef Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou D, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 2015;18:145–53.PubMedCrossRef
21.
Zurück zum Zitat Yasui M, Shiraishi Y, Ozaki N, Hayashi K, Hori K, Ichiyanagi M, et al. Nerve growth factor and associated nerve sprouting contribute to local mechanical hyperalgesia in a rat model of bone injury. Eur J Pain. 2012;16:953–65.PubMedCrossRef Yasui M, Shiraishi Y, Ozaki N, Hayashi K, Hori K, Ichiyanagi M, et al. Nerve growth factor and associated nerve sprouting contribute to local mechanical hyperalgesia in a rat model of bone injury. Eur J Pain. 2012;16:953–65.PubMedCrossRef
22.
23.
Zurück zum Zitat Jimenez-Andrade JM, Bloom AP, Mantyh WG, Koewler NJ, Freeman KT, Delong D, et al. Capsaicin-sensitive sensory nerve fibers contribute to the generation and maintenance of skeletal fracture pain. Neuroscience. 2009;162:1244–54.PubMedCrossRef Jimenez-Andrade JM, Bloom AP, Mantyh WG, Koewler NJ, Freeman KT, Delong D, et al. Capsaicin-sensitive sensory nerve fibers contribute to the generation and maintenance of skeletal fracture pain. Neuroscience. 2009;162:1244–54.PubMedCrossRef
24.
Zurück zum Zitat Lee S, Hwang C, Marini S, Tower RJ, Qin Q, Negri S, et al. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun. 2021;12:4939.PubMedPubMedCentralCrossRef Lee S, Hwang C, Marini S, Tower RJ, Qin Q, Negri S, et al. NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma. Nat Commun. 2021;12:4939.PubMedPubMedCentralCrossRef
25.
Zurück zum Zitat Chartier SR, Mitchell SA, Majuta LA, Mantyh PW. Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur. Mol Pain. 2017;13:1744806917745465.PubMedPubMedCentralCrossRef Chartier SR, Mitchell SA, Majuta LA, Mantyh PW. Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur. Mol Pain. 2017;13:1744806917745465.PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat •Meyers CA, Lee S, Sono T, Xu J, Negri S, Tian Y, et al. A neurotrophic mechanism directs sensory nerve transit in cranial bone. Cell Rep. 2020;31:107696. Using a cranial defect model, the authors highlighted the role of NGF-expressing cells during intramembranous bone regeneration. The inhibition of the NGF signaling pathway negatively affected the re-innervation and skeletal healing. •Meyers CA, Lee S, Sono T, Xu J, Negri S, Tian Y, et al. A neurotrophic mechanism directs sensory nerve transit in cranial bone. Cell Rep. 2020;31:107696. Using a cranial defect model, the authors highlighted the role of NGF-expressing cells during intramembranous bone regeneration. The inhibition of the NGF signaling pathway negatively affected the re-innervation and skeletal healing.
27.
Zurück zum Zitat Li Z, Meyers CA, Chang L, Lee S, Li Z, Tomlinson R, et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest. 2019;129:5137–50.PubMedPubMedCentralCrossRef Li Z, Meyers CA, Chang L, Lee S, Li Z, Tomlinson R, et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest. 2019;129:5137–50.PubMedPubMedCentralCrossRef
28.
Zurück zum Zitat Asaumi K, Nakanishi T, Asahara H, Inoue H, Takigawa M. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone. 2000;26:625–33.PubMedCrossRef Asaumi K, Nakanishi T, Asahara H, Inoue H, Takigawa M. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone. 2000;26:625–33.PubMedCrossRef
29.
Zurück zum Zitat Aiga A, Asaumi K, Lee Y-J, Kadota H, Mitani S, Ozaki T, et al. Expression of neurotrophins and their receptors tropomyosin-related kinases (Trk) under tension-stress during distraction osteogenesis. Acta Med Okayama. 2006;60:267–77.PubMed Aiga A, Asaumi K, Lee Y-J, Kadota H, Mitani S, Ozaki T, et al. Expression of neurotrophins and their receptors tropomyosin-related kinases (Trk) under tension-stress during distraction osteogenesis. Acta Med Okayama. 2006;60:267–77.PubMed
30.
Zurück zum Zitat Cantarella G, Lempereur L, Presta M, Ribatti D, Lombardo G, Lazarovici P, et al. Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo. FASEB J. 2002;16:1307–9.PubMedCrossRef Cantarella G, Lempereur L, Presta M, Ribatti D, Lombardo G, Lazarovici P, et al. Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo. FASEB J. 2002;16:1307–9.PubMedCrossRef
31.
Zurück zum Zitat Zhu S, Zhu J, Zhen G, Hu Y, An S, Li Y, et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J Clin Invest. 2019;129:1076–93.PubMedPubMedCentralCrossRef Zhu S, Zhu J, Zhen G, Hu Y, An S, Li Y, et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J Clin Invest. 2019;129:1076–93.PubMedPubMedCentralCrossRef
32.
Zurück zum Zitat Kenan S, Onur ÖD, Solakoğlu S, Kotil T, Ramazanoğlu M, Çelik HH, et al. Investigation of the effects of semaphorin 3A on new bone formation in a rat calvarial defect model. J Craniomaxillofac Surg. 2019;47:473–83.PubMedCrossRef Kenan S, Onur ÖD, Solakoğlu S, Kotil T, Ramazanoğlu M, Çelik HH, et al. Investigation of the effects of semaphorin 3A on new bone formation in a rat calvarial defect model. J Craniomaxillofac Surg. 2019;47:473–83.PubMedCrossRef
33.
Zurück zum Zitat Tear G. Molecular cues that guide the development of neural connectivity. Essays Biochem. 1998;33:1–13.PubMedCrossRef Tear G. Molecular cues that guide the development of neural connectivity. Essays Biochem. 1998;33:1–13.PubMedCrossRef
34.
Zurück zum Zitat McDonald AC, Schuijers JA, Shen P-J, Gundlach AL, Grills BL. Expression of galanin and galanin receptor-1 in normal bone and during fracture repair in the rat. Bone. 2003;33:788–97.PubMedCrossRef McDonald AC, Schuijers JA, Shen P-J, Gundlach AL, Grills BL. Expression of galanin and galanin receptor-1 in normal bone and during fracture repair in the rat. Bone. 2003;33:788–97.PubMedCrossRef
35.
Zurück zum Zitat Park KW, Crouse D, Lee M, Karnik SK, Sorensen LK, Murphy KJ, et al. The axonal attractant netrin-1 is an angiogenic factor. Proc Natl Acad Sci USA. 2004;101:16210–5.PubMedPubMedCentralCrossRef Park KW, Crouse D, Lee M, Karnik SK, Sorensen LK, Murphy KJ, et al. The axonal attractant netrin-1 is an angiogenic factor. Proc Natl Acad Sci USA. 2004;101:16210–5.PubMedPubMedCentralCrossRef
36.
Zurück zum Zitat Zheng S, Li W, Xu M, Bai X, Zhou Z, Han J, et al. Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase. Am J Physiol, Cell Physiol. 2010;299:C1485–92.PubMedCrossRef Zheng S, Li W, Xu M, Bai X, Zhou Z, Han J, et al. Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase. Am J Physiol, Cell Physiol. 2010;299:C1485–92.PubMedCrossRef
37.
Zurück zum Zitat Li J, Kreicbergs A, Bergström J, Stark A, Ahmed M. Site-specific CGRP innervation coincides with bone formation during fracture healing and modeling: a study in rat angulated tibia. J Orthop Res. 2007;25:1204–12.PubMedCrossRef Li J, Kreicbergs A, Bergström J, Stark A, Ahmed M. Site-specific CGRP innervation coincides with bone formation during fracture healing and modeling: a study in rat angulated tibia. J Orthop Res. 2007;25:1204–12.PubMedCrossRef
38.
Zurück zum Zitat Long H, Ahmed M, Ackermann P, Stark A, Li J. Neuropeptide Y innervation during fracture healing and remodeling. A study of angulated tibial fractures in the rat. Acta Orthop. 2010;81:639–46.PubMedPubMedCentralCrossRef Long H, Ahmed M, Ackermann P, Stark A, Li J. Neuropeptide Y innervation during fracture healing and remodeling. A study of angulated tibial fractures in the rat. Acta Orthop. 2010;81:639–46.PubMedPubMedCentralCrossRef
39.
Zurück zum Zitat Li J, Ahmad T, Spetea M, Ahmed M, Kreicbergs A. Bone reinnervation after fracture: a study in the rat. J Bone Miner Res. 2001;16:1505–10.PubMedCrossRef Li J, Ahmad T, Spetea M, Ahmed M, Kreicbergs A. Bone reinnervation after fracture: a study in the rat. J Bone Miner Res. 2001;16:1505–10.PubMedCrossRef
40.
Zurück zum Zitat Hukkanen M, Konttinen YT, Santavirta S, Paavolainen P, Gu XH, Terenghi G, et al. Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience. 1993;54:969–79.PubMedCrossRef Hukkanen M, Konttinen YT, Santavirta S, Paavolainen P, Gu XH, Terenghi G, et al. Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience. 1993;54:969–79.PubMedCrossRef
41.
Zurück zum Zitat Grills BL, Schuijers JA, Ward AR. Topical application of nerve growth factor improves fracture healing in rats. J Orthop Res. 1997;15:235–42.PubMedCrossRef Grills BL, Schuijers JA, Ward AR. Topical application of nerve growth factor improves fracture healing in rats. J Orthop Res. 1997;15:235–42.PubMedCrossRef
42.
Zurück zum Zitat Santavirta S, Konttinen YT, Nordström D, Mäkelä A, Sorsa T, Hukkanen M, et al. Immunologic studies of nonunited fractures. Acta Orthop. 1992;63:579–86.CrossRef Santavirta S, Konttinen YT, Nordström D, Mäkelä A, Sorsa T, Hukkanen M, et al. Immunologic studies of nonunited fractures. Acta Orthop. 1992;63:579–86.CrossRef
43.
Zurück zum Zitat Chartier SR, Thompson ML, Longo G, Fealk MN, Majuta LA, Mantyh PW. Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain. Pain. 2014;155:2323–36.PubMedPubMedCentralCrossRef Chartier SR, Thompson ML, Longo G, Fealk MN, Majuta LA, Mantyh PW. Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain. Pain. 2014;155:2323–36.PubMedPubMedCentralCrossRef
44.
Zurück zum Zitat Thompson DW. On growth and form. UK, London: Cambridge University Press; 1917. Thompson DW. On growth and form. UK, London: Cambridge University Press; 1917.
45.
Zurück zum Zitat Grey EG, Carr GL. An experimental study of the factors responsible for noninfectious bone atrophy. Bull Johns Hopkins Hosp. 1915;26:381–5. Grey EG, Carr GL. An experimental study of the factors responsible for noninfectious bone atrophy. Bull Johns Hopkins Hosp. 1915;26:381–5.
46.
Zurück zum Zitat • Yang Y, Zhou J, Liang C, Xiao Q, Chen Y, Yu B. Effects of highly selective sensory/motor nerve injury on bone metabolism and bone remodeling in rats. J Musculoskelet Neuronal Interact. 2022;22:524–35. This paper performs selective denervation of sensory or motor roots (or both) in rats prior to analysis of changes in bone. This is notable given the precision of the surgeries and shows a progressive increase in osteoclast recruitment with different surgical approaches.PubMedPubMedCentral • Yang Y, Zhou J, Liang C, Xiao Q, Chen Y, Yu B. Effects of highly selective sensory/motor nerve injury on bone metabolism and bone remodeling in rats. J Musculoskelet Neuronal Interact. 2022;22:524–35. This paper performs selective denervation of sensory or motor roots (or both) in rats prior to analysis of changes in bone. This is notable given the precision of the surgeries and shows a progressive increase in osteoclast recruitment with different surgical approaches.PubMedPubMedCentral
47.
Zurück zum Zitat Madsen JE, Hukkanen M, Aune AK, Basran I, Møller JF, Polak JM, et al. Fracture healing and callus innervation after peripheral nerve resection in rats. Clin Orthop Relat Res. 1998;(351):230–40. Madsen JE, Hukkanen M, Aune AK, Basran I, Møller JF, Polak JM, et al. Fracture healing and callus innervation after peripheral nerve resection in rats. Clin Orthop Relat Res. 1998;(351):230–40.
48.
Zurück zum Zitat Chiego DJ, Singh IJ. Evaluation of the effects of sensory denervation on osteoblasts by 3H-proline autoradiography. Cell Tissue Res. 1981;217:569–76.PubMedCrossRef Chiego DJ, Singh IJ. Evaluation of the effects of sensory denervation on osteoblasts by 3H-proline autoradiography. Cell Tissue Res. 1981;217:569–76.PubMedCrossRef
49.
Zurück zum Zitat Xu Y, Xia M, Chen T, Yang Y, Fu G, Ji P, et al. Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction. Ann N Y Acad Sci. 2019;1448:52–64.PubMedCrossRef Xu Y, Xia M, Chen T, Yang Y, Fu G, Ji P, et al. Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction. Ann N Y Acad Sci. 2019;1448:52–64.PubMedCrossRef
50.
Zurück zum Zitat Cao J, Zhang S, Gupta A, Du Z, Lei D, Wang L, et al. Sensory nerves affect bone regeneration in rabbit mandibular distraction osteogenesis. Int J Med Sci. 2019;16:831–7.PubMedPubMedCentralCrossRef Cao J, Zhang S, Gupta A, Du Z, Lei D, Wang L, et al. Sensory nerves affect bone regeneration in rabbit mandibular distraction osteogenesis. Int J Med Sci. 2019;16:831–7.PubMedPubMedCentralCrossRef
51.
Zurück zum Zitat Song D, Jiang X, Zhu S, Li W, Khadka A, Hu J. Denervation impairs bone regeneration during distraction osteogenesis in rabbit tibia lengthening. Acta Orthop. 2012;83:406–10.PubMedPubMedCentralCrossRef Song D, Jiang X, Zhu S, Li W, Khadka A, Hu J. Denervation impairs bone regeneration during distraction osteogenesis in rabbit tibia lengthening. Acta Orthop. 2012;83:406–10.PubMedPubMedCentralCrossRef
52.
Zurück zum Zitat Tevlin R, Griffin M, Chen K, Januszyk M, Guardino N, Spielman A, et al. Denervation during mandibular distraction osteogenesis results in impaired bone formation. Sci Rep. 2023;13:2097.PubMedPubMedCentralCrossRef Tevlin R, Griffin M, Chen K, Januszyk M, Guardino N, Spielman A, et al. Denervation during mandibular distraction osteogenesis results in impaired bone formation. Sci Rep. 2023;13:2097.PubMedPubMedCentralCrossRef
53.
Zurück zum Zitat Zhang D, Zhang P, Wang Y, Han N, Tang C, Jiang B. The influence of brain injury or peripheral nerve injury on calcitonin gene-related peptide concentration variation and fractures healing process. Artif Cells Blood Substit Immobil Biotechnol. 2009;37:85–91.PubMedCrossRef Zhang D, Zhang P, Wang Y, Han N, Tang C, Jiang B. The influence of brain injury or peripheral nerve injury on calcitonin gene-related peptide concentration variation and fractures healing process. Artif Cells Blood Substit Immobil Biotechnol. 2009;37:85–91.PubMedCrossRef
54.
Zurück zum Zitat Al-Harby SW, Samy MT, El Naggar MI, Al-Demagh SA, Nooreldin MA. Delayed healing of experiment fractures in the denervated limbs of dogs. Bahrain Med Bull. 1996;18:1. Al-Harby SW, Samy MT, El Naggar MI, Al-Demagh SA, Nooreldin MA. Delayed healing of experiment fractures in the denervated limbs of dogs. Bahrain Med Bull. 1996;18:1.
55.
Zurück zum Zitat Gkiatas I, Kostas-Agnantis I, Agathopoulos S, Papadopoulos D, Vekris M, Gelalis I, et al. The effect of peripheral nervous system in growing bone biomechanics. An experimental study. J Orthop. 2019;16:289–92.PubMedPubMedCentralCrossRef Gkiatas I, Kostas-Agnantis I, Agathopoulos S, Papadopoulos D, Vekris M, Gelalis I, et al. The effect of peripheral nervous system in growing bone biomechanics. An experimental study. J Orthop. 2019;16:289–92.PubMedPubMedCentralCrossRef
56.
Zurück zum Zitat Ma S, Li J, Guo Y, Huang Y, Chi X, Wei Y, et al. Three-dimensional radiographic and histological tracking of rat mandibular defect repair after inferior alveolar nerve axotomy. Arch Oral Biol. 2021;131: 105252.PubMedCrossRef Ma S, Li J, Guo Y, Huang Y, Chi X, Wei Y, et al. Three-dimensional radiographic and histological tracking of rat mandibular defect repair after inferior alveolar nerve axotomy. Arch Oral Biol. 2021;131: 105252.PubMedCrossRef
57.
Zurück zum Zitat Wu Q, Yang B, Cao C, Guang M, Gong P. Age-dependent impact of inferior alveolar nerve transection on mandibular bone metabolism and the underlying mechanisms. J Mol Histol. 2016;47:579–86.PubMedCrossRef Wu Q, Yang B, Cao C, Guang M, Gong P. Age-dependent impact of inferior alveolar nerve transection on mandibular bone metabolism and the underlying mechanisms. J Mol Histol. 2016;47:579–86.PubMedCrossRef
58.
Zurück zum Zitat Frymoyer JW, Pope MH. Fracture healing in the sciatically denervated rat. J Trauma. 1977;17:355–61.PubMedCrossRef Frymoyer JW, Pope MH. Fracture healing in the sciatically denervated rat. J Trauma. 1977;17:355–61.PubMedCrossRef
59.
Zurück zum Zitat Aro H. Effect of nerve injury on fracture healing. Callus formation studied in the rat. Acta Orthop Scand. 1985;56:233–7.PubMedCrossRef Aro H. Effect of nerve injury on fracture healing. Callus formation studied in the rat. Acta Orthop Scand. 1985;56:233–7.PubMedCrossRef
60.
Zurück zum Zitat Farkas JE, Freitas PD, Bryant DM, Whited JL, Monaghan JR. Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration. Development. 2016;143:2724–31.PubMed Farkas JE, Freitas PD, Bryant DM, Whited JL, Monaghan JR. Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration. Development. 2016;143:2724–31.PubMed
61.
Zurück zum Zitat •• Dolan CP, Yan M, Zimmel K, Yang T-J, Leininger E, Dawson LA, et al. Axonal regrowth is impaired during digit tip regeneration in mice. Dev Biol. 2019;445:237–44. This paper clarifies prior literature to reveal that denervation of the digit tip impairs soft tissue wound closure but does not impair bone formation directly. When synthetic wound closure is achieved, bone regenerates normally even in the absence of innervation.PubMedCrossRef •• Dolan CP, Yan M, Zimmel K, Yang T-J, Leininger E, Dawson LA, et al. Axonal regrowth is impaired during digit tip regeneration in mice. Dev Biol. 2019;445:237–44. This paper clarifies prior literature to reveal that denervation of the digit tip impairs soft tissue wound closure but does not impair bone formation directly. When synthetic wound closure is achieved, bone regenerates normally even in the absence of innervation.PubMedCrossRef
63.
Zurück zum Zitat Dolan CP, Imholt F, Yan M, Yang T-J, Gregory J, Qureshi O, et al. Digit specific denervation does not inhibit mouse digit tip regeneration. Dev Biol. 2022;486:71–80.PubMedPubMedCentralCrossRef Dolan CP, Imholt F, Yan M, Yang T-J, Gregory J, Qureshi O, et al. Digit specific denervation does not inhibit mouse digit tip regeneration. Dev Biol. 2022;486:71–80.PubMedPubMedCentralCrossRef
64.
Zurück zum Zitat Key JA, Moore RM. Healing of fractures, of defects in bone and of defects in cartilage after sympathectomy. Arch Surg. 1933;26:272–9.CrossRef Key JA, Moore RM. Healing of fractures, of defects in bone and of defects in cartilage after sympathectomy. Arch Surg. 1933;26:272–9.CrossRef
65.
Zurück zum Zitat Kizilay H, Cakici H, Kilinc E, Firat T, Kuru T, Sahin AA. Effects of stellate ganglion block on healing of fractures induced in rats. Biomed Res Int. 2020;2020:4503463.PubMedPubMedCentralCrossRef Kizilay H, Cakici H, Kilinc E, Firat T, Kuru T, Sahin AA. Effects of stellate ganglion block on healing of fractures induced in rats. Biomed Res Int. 2020;2020:4503463.PubMedPubMedCentralCrossRef
66.
Zurück zum Zitat Corbin KB, Hinsey JC. Influence of the nervous system on bone and joints. Anat Rec. 1939;75:307–17.CrossRef Corbin KB, Hinsey JC. Influence of the nervous system on bone and joints. Anat Rec. 1939;75:307–17.CrossRef
67.
Zurück zum Zitat Zollinger R. Effect of lumbar ganglionectomy upon repair of bone. Am J Surg. 1933;20:70–6.CrossRef Zollinger R. Effect of lumbar ganglionectomy upon repair of bone. Am J Surg. 1933;20:70–6.CrossRef
68.
Zurück zum Zitat Pearse HE, Morton JJ. The stimulation of bone growth by venous stasis. J. Bone Joint Surg. 1930;12:97. Pearse HE, Morton JJ. The stimulation of bone growth by venous stasis. J. Bone Joint Surg. 1930;12:97.
69.
Zurück zum Zitat Wang T, Cao J, Du Z, Zhang Y, Liu Y, Wang L, et al. Effects of sympathetic innervation loss on mandibular distraction osteogenesis. J Craniofac Surg. 2012;23:1524–8.PubMedCrossRef Wang T, Cao J, Du Z, Zhang Y, Liu Y, Wang L, et al. Effects of sympathetic innervation loss on mandibular distraction osteogenesis. J Craniofac Surg. 2012;23:1524–8.PubMedCrossRef
70.
Zurück zum Zitat Du Z, Wang L, Zhao Y, Cao J, Wang T, Liu P, et al. Sympathetic denervation-induced MSC mobilization in distraction osteogenesis associates with inhibition of MSC migration and osteogenesis by norepinephrine/adrb3. PLoS ONE. 2014;9: e105976.PubMedPubMedCentralCrossRef Du Z, Wang L, Zhao Y, Cao J, Wang T, Liu P, et al. Sympathetic denervation-induced MSC mobilization in distraction osteogenesis associates with inhibition of MSC migration and osteogenesis by norepinephrine/adrb3. PLoS ONE. 2014;9: e105976.PubMedPubMedCentralCrossRef
71.
Zurück zum Zitat Ito H, Asami G. Lumbosacral sympathetic ganglionectomy its value as a therapeutic measure for thromboangiitis obliterans (with a sidelight upon alleged sympathetic innervation of the tonus of the skeletal muscles). Am J Surg. 1932;15:26–38.CrossRef Ito H, Asami G. Lumbosacral sympathetic ganglionectomy its value as a therapeutic measure for thromboangiitis obliterans (with a sidelight upon alleged sympathetic innervation of the tonus of the skeletal muscles). Am J Surg. 1932;15:26–38.CrossRef
72.
Zurück zum Zitat Harris RI, Mcdonald JL. The effect of lumbar sympathectomy upon the growth of legs paralyzed by anterior poliomyelitis. J Bone Joint Surg. 1936 Harris RI, Mcdonald JL. The effect of lumbar sympathectomy upon the growth of legs paralyzed by anterior poliomyelitis. J Bone Joint Surg. 1936
73.
Zurück zum Zitat Colp R. Periarterial sympathectomy in fractures. Arch Surg. 1933;27:658.CrossRef Colp R. Periarterial sympathectomy in fractures. Arch Surg. 1933;27:658.CrossRef
74.
Zurück zum Zitat Colp R. Experiences with periarterial sympathectomy in fractures of the lower extremity. JAMA. 1931;97:1069.CrossRef Colp R. Experiences with periarterial sympathectomy in fractures of the lower extremity. JAMA. 1931;97:1069.CrossRef
75.
Zurück zum Zitat Shi L, Liu Y, Yang Z, Wu T, Lo HT, Xu J, et al. Vasoactive intestinal peptide promotes fracture healing in sympathectomized mice. Calcif Tissue Int. 2021;109:55–65.PubMedCrossRef Shi L, Liu Y, Yang Z, Wu T, Lo HT, Xu J, et al. Vasoactive intestinal peptide promotes fracture healing in sympathectomized mice. Calcif Tissue Int. 2021;109:55–65.PubMedCrossRef
77.
Zurück zum Zitat Scammell BE. A study of sympathectomy and fracture repair [Doctoral dissertation]. University of Southampton. United Kingdom. 1994. Scammell BE. A study of sympathectomy and fracture repair [Doctoral dissertation]. University of Southampton. United Kingdom. 1994.
78.
Zurück zum Zitat Guan Z, Yuan W, Jia J, Zhang C, Zhu J, Huang J, et al. Bone mass loss in chronic heart failure is associated with sympathetic nerve activation. Bone. 2023;166: 116596.PubMedCrossRef Guan Z, Yuan W, Jia J, Zhang C, Zhu J, Huang J, et al. Bone mass loss in chronic heart failure is associated with sympathetic nerve activation. Bone. 2023;166: 116596.PubMedCrossRef
79.
Zurück zum Zitat Cherruau M, Facchinetti P, Baroukh B, Saffar JL. Chemical sympathectomy impairs bone resorption in rats: a role for the sympathetic system on bone metabolism. Bone. 1999;25:545–51.PubMedCrossRef Cherruau M, Facchinetti P, Baroukh B, Saffar JL. Chemical sympathectomy impairs bone resorption in rats: a role for the sympathetic system on bone metabolism. Bone. 1999;25:545–51.PubMedCrossRef
80.
Zurück zum Zitat Hill EL, Turner R, Elde R. Effects of neonatal sympathectomy and capsaicin treatment on bone remodeling in rats. Neuroscience. 1991;44:747–55.PubMedCrossRef Hill EL, Turner R, Elde R. Effects of neonatal sympathectomy and capsaicin treatment on bone remodeling in rats. Neuroscience. 1991;44:747–55.PubMedCrossRef
83.
Zurück zum Zitat Corbin KB. Alterations in the hip joint after deafferentation. Arch Surg. 1937;35:1145.CrossRef Corbin KB. Alterations in the hip joint after deafferentation. Arch Surg. 1937;35:1145.CrossRef
84.
Zurück zum Zitat Zhang Z-K, Guo X, Lao J, Qin Y-X. Effect of capsaicin-sensitive sensory neurons on bone architecture and mechanical properties in the rat hindlimb suspension model. J Orthop Translat. 2017;10:12–7.PubMedPubMedCentralCrossRef Zhang Z-K, Guo X, Lao J, Qin Y-X. Effect of capsaicin-sensitive sensory neurons on bone architecture and mechanical properties in the rat hindlimb suspension model. J Orthop Translat. 2017;10:12–7.PubMedPubMedCentralCrossRef
85.
Zurück zum Zitat Hu B, Lv X, Chen H, Xue P, Gao B, Wang X, et al. Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones. J Clin Invest. 2020;130:3483–98.PubMedPubMedCentralCrossRef Hu B, Lv X, Chen H, Xue P, Gao B, Wang X, et al. Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones. J Clin Invest. 2020;130:3483–98.PubMedPubMedCentralCrossRef
86.
Zurück zum Zitat Apel PJ, Crane D, Northam CN, Callahan M, Smith TL, Teasdall RD. Effect of selective sensory denervation on fracture-healing: an experimental study of rats. J Bone Joint Surg Am. 2009;91:2886–95.PubMedCrossRef Apel PJ, Crane D, Northam CN, Callahan M, Smith TL, Teasdall RD. Effect of selective sensory denervation on fracture-healing: an experimental study of rats. J Bone Joint Surg Am. 2009;91:2886–95.PubMedCrossRef
87.
Zurück zum Zitat Huang B, Ye J, Zeng X, Gong P. Effects of capsaicin-induced sensory denervation on early implant osseointegration in adult rats. R Soc Open Sci. 2019;6: 181082.PubMedPubMedCentralCrossRef Huang B, Ye J, Zeng X, Gong P. Effects of capsaicin-induced sensory denervation on early implant osseointegration in adult rats. R Soc Open Sci. 2019;6: 181082.PubMedPubMedCentralCrossRef
88.
Zurück zum Zitat Offley SC, Guo T-Z, Wei T, Clark JD, Vogel H, Lindsey DP, et al. Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. J Bone Miner Res. 2005;20:257–67.PubMedCrossRef Offley SC, Guo T-Z, Wei T, Clark JD, Vogel H, Lindsey DP, et al. Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. J Bone Miner Res. 2005;20:257–67.PubMedCrossRef
89.
Zurück zum Zitat Ding Y, Arai M, Kondo H, Togari A. Effects of capsaicin-induced sensory denervation on bone metabolism in adult rats. Bone. 2010;46:1591–6.PubMedCrossRef Ding Y, Arai M, Kondo H, Togari A. Effects of capsaicin-induced sensory denervation on bone metabolism in adult rats. Bone. 2010;46:1591–6.PubMedCrossRef
90.
Zurück zum Zitat Heffner MA, Anderson MJ, Yeh GC, Genetos DC, Christiansen BA. Altered bone development in a mouse model of peripheral sensory nerve inactivation. J Musculoskelet Neuronal Interact. 2014;14:1–9.PubMed Heffner MA, Anderson MJ, Yeh GC, Genetos DC, Christiansen BA. Altered bone development in a mouse model of peripheral sensory nerve inactivation. J Musculoskelet Neuronal Interact. 2014;14:1–9.PubMed
91.
Zurück zum Zitat Chen H, Hu B, Lv X, Zhu S, Zhen G, Wan M, et al. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat Commun. 2019;10:181.PubMedPubMedCentralCrossRef Chen H, Hu B, Lv X, Zhu S, Zhen G, Wan M, et al. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat Commun. 2019;10:181.PubMedPubMedCentralCrossRef
92.
Zurück zum Zitat • Kwun-Tung Ng T, Chan W-S, Peng PWH, Sham P, Sasaki S, Tsui H-F. Chemical hip denervation for inoperable hip fracture. Anesth Analg. 2020;130:498–504. This paper highlights local denervation as an emerging technique to combat pain and limited mobility in patients with hip fracture. This highlights the fact that denervation may have important benefits to the patient that do not substantially impair local healing responses in humans.PubMedCrossRef • Kwun-Tung Ng T, Chan W-S, Peng PWH, Sham P, Sasaki S, Tsui H-F. Chemical hip denervation for inoperable hip fracture. Anesth Analg. 2020;130:498–504. This paper highlights local denervation as an emerging technique to combat pain and limited mobility in patients with hip fracture. This highlights the fact that denervation may have important benefits to the patient that do not substantially impair local healing responses in humans.PubMedCrossRef
93.
Zurück zum Zitat Ng TK-T, Peng P, Chan W-S. Posterior hip pericapsular neurolysis (PHPN) for inoperable hip fracture: an adjunct to anterior hip pericapsular neurolysis. Reg Anesth Pain Med. 2021;46:1080–4.PubMedCrossRef Ng TK-T, Peng P, Chan W-S. Posterior hip pericapsular neurolysis (PHPN) for inoperable hip fracture: an adjunct to anterior hip pericapsular neurolysis. Reg Anesth Pain Med. 2021;46:1080–4.PubMedCrossRef
94.
Zurück zum Zitat Li Y, Hoffman MD, Benoit DSW. Matrix metalloproteinase (MMP)-degradable tissue engineered periosteum coordinates allograft healing via early stage recruitment and support of host neurovasculature. Biomaterials. 2021;268: 120535.PubMedCrossRef Li Y, Hoffman MD, Benoit DSW. Matrix metalloproteinase (MMP)-degradable tissue engineered periosteum coordinates allograft healing via early stage recruitment and support of host neurovasculature. Biomaterials. 2021;268: 120535.PubMedCrossRef
95.
Zurück zum Zitat Fan J, Mu T, Qin J, Bi L, Pei G. Different effects of implanting sensory nerve or blood vessel on the vascularization, neurotization, and osteogenesis of tissue-engineered bone in vivo. Biomed Res Int. 2014;2014: 412570.PubMedPubMedCentralCrossRef Fan J, Mu T, Qin J, Bi L, Pei G. Different effects of implanting sensory nerve or blood vessel on the vascularization, neurotization, and osteogenesis of tissue-engineered bone in vivo. Biomed Res Int. 2014;2014: 412570.PubMedPubMedCentralCrossRef
96.
Zurück zum Zitat Chen S-Y, Qin J-J, Wang L, Mu T-W, Jin D, Jiang S, et al. Different effects of implanting vascular bundles and sensory nerve tracts on the expression of neuropeptide receptors in tissue-engineered bone in vivo. Biomed Mater. 2010;5: 055002.PubMedCrossRef Chen S-Y, Qin J-J, Wang L, Mu T-W, Jin D, Jiang S, et al. Different effects of implanting vascular bundles and sensory nerve tracts on the expression of neuropeptide receptors in tissue-engineered bone in vivo. Biomed Mater. 2010;5: 055002.PubMedCrossRef
97.
Zurück zum Zitat Feng L, Lingling E, Liu H. The effects of separating inferior alveolar neurovascular bundles on osteogenesis of tissue-engineered bone and vascularization. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159:637–41.PubMedCrossRef Feng L, Lingling E, Liu H. The effects of separating inferior alveolar neurovascular bundles on osteogenesis of tissue-engineered bone and vascularization. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159:637–41.PubMedCrossRef
98.
Zurück zum Zitat Wu Y, Jing D, Ouyang H, Li L, Zhai M, Li Y, et al. Pre-implanted sensory nerve could enhance the neurotization in tissue-engineered bone graft. Tissue Eng Part A. 2015;21:2241–9.PubMedCrossRef Wu Y, Jing D, Ouyang H, Li L, Zhai M, Li Y, et al. Pre-implanted sensory nerve could enhance the neurotization in tissue-engineered bone graft. Tissue Eng Part A. 2015;21:2241–9.PubMedCrossRef
99.
Zurück zum Zitat Xu J, Wang J, Chen X, Li Y, Mi J, Qin L. The effects of calcitonin gene-related peptide on bone homeostasis and regeneration. Curr Osteoporos Rep. 2020;18:621–32.PubMedCrossRef Xu J, Wang J, Chen X, Li Y, Mi J, Qin L. The effects of calcitonin gene-related peptide on bone homeostasis and regeneration. Curr Osteoporos Rep. 2020;18:621–32.PubMedCrossRef
100.
Zurück zum Zitat Wee NKY, Novak S, Ghosh D, Root SH, Dickerson IM, Kalajzic I. Inhibition of CGRP signaling impairs fracture healing in mice. J Orthop Res. 2023;41:1228–39.PubMedCrossRef Wee NKY, Novak S, Ghosh D, Root SH, Dickerson IM, Kalajzic I. Inhibition of CGRP signaling impairs fracture healing in mice. J Orthop Res. 2023;41:1228–39.PubMedCrossRef
101.
Zurück zum Zitat Appelt J, Baranowsky A, Jahn D, Yorgan T, Köhli P, Otto E, et al. The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing. EBioMedicine. 2020;59: 102970.PubMedPubMedCentralCrossRef Appelt J, Baranowsky A, Jahn D, Yorgan T, Köhli P, Otto E, et al. The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing. EBioMedicine. 2020;59: 102970.PubMedPubMedCentralCrossRef
102.
Zurück zum Zitat •• Zheng N, Xu J, Ruan YC, Chang L, Wang X, Yao H, et al. Magnesium facilitates the healing of atypical femoral fractures: a single-cell transcriptomic study. Mater Today. 2022;52:43–62. This paper uses single-cell RNA sequencing to identify the cell type responsible for irregular healing found in atypical femoral fractures. Furthermore, they showed that CGRP treatment, either through exogenous injection or through endogenous stimulation using a Mg intramedullary nail fixation system, could reduce the non-healing phenotype, demonstrating the key role of CGRP in fracture healing.CrossRef •• Zheng N, Xu J, Ruan YC, Chang L, Wang X, Yao H, et al. Magnesium facilitates the healing of atypical femoral fractures: a single-cell transcriptomic study. Mater Today. 2022;52:43–62. This paper uses single-cell RNA sequencing to identify the cell type responsible for irregular healing found in atypical femoral fractures. Furthermore, they showed that CGRP treatment, either through exogenous injection or through endogenous stimulation using a Mg intramedullary nail fixation system, could reduce the non-healing phenotype, demonstrating the key role of CGRP in fracture healing.CrossRef
103.
Zurück zum Zitat Zhang Y, Xu J, Ruan YC, Yu MK, O’Laughlin M, Wise H, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat Med. 2016;22:1160–9.PubMedPubMedCentralCrossRef Zhang Y, Xu J, Ruan YC, Yu MK, O’Laughlin M, Wise H, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat Med. 2016;22:1160–9.PubMedPubMedCentralCrossRef
104.
Zurück zum Zitat •• Qiao W, Pan D, Zheng Y, Wu S, Liu X, Chen Z, et al. Divalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models. Nat Commun. 2022;13:535. This paper eloquently identifies the mechanism through which divalent cations found in bone implants stimulate bone healing. The authors propose a model whereby macrophages signal to CGRP+ nerves to send signals to the hypothalamus that downregulate sympathetic tone and encourage bone formation.PubMedPubMedCentralCrossRef •• Qiao W, Pan D, Zheng Y, Wu S, Liu X, Chen Z, et al. Divalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models. Nat Commun. 2022;13:535. This paper eloquently identifies the mechanism through which divalent cations found in bone implants stimulate bone healing. The authors propose a model whereby macrophages signal to CGRP+ nerves to send signals to the hypothalamus that downregulate sympathetic tone and encourage bone formation.PubMedPubMedCentralCrossRef
105.
Zurück zum Zitat •• Mi J, Xu J-K, Yao Z, Yao H, Li Y, He X, et al. Implantable electrical stimulation at dorsal root ganglions accelerates osteoporotic fracture healing via calcitonin gene-related peptide. Adv Sci (Weinh). 2022;9: e2103005. This paper uses a unique approach to stimulate neuropeptide signaling through electrical stimulation in the dorsal root ganglia. Implantable electrical stimulation for 2 weeks following fracture enhanced CGRP secretion, type H vessel formation, and fracture healing.PubMedCrossRef •• Mi J, Xu J-K, Yao Z, Yao H, Li Y, He X, et al. Implantable electrical stimulation at dorsal root ganglions accelerates osteoporotic fracture healing via calcitonin gene-related peptide. Adv Sci (Weinh). 2022;9: e2103005. This paper uses a unique approach to stimulate neuropeptide signaling through electrical stimulation in the dorsal root ganglia. Implantable electrical stimulation for 2 weeks following fracture enhanced CGRP secretion, type H vessel formation, and fracture healing.PubMedCrossRef
106.
Zurück zum Zitat Tang P, Duan C, Wang Z, Wang C, Meng G, Lin K, et al. NPY and CGRP inhibitor influence on ERK pathway and macrophage aggregation during fracture healing. Cell Physiol Biochem. 2017;41:1457–67.PubMedCrossRef Tang P, Duan C, Wang Z, Wang C, Meng G, Lin K, et al. NPY and CGRP inhibitor influence on ERK pathway and macrophage aggregation during fracture healing. Cell Physiol Biochem. 2017;41:1457–67.PubMedCrossRef
107.
Zurück zum Zitat Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158:543–59.PubMedPubMedCentralCrossRef Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158:543–59.PubMedPubMedCentralCrossRef
109.
Zurück zum Zitat Johnston APW, Yuzwa SA, Carr MJ, Mahmud N, Storer MA, Krause MP, et al. Dedifferentiated Schwann cell precursors secreting paracrine factors are required for regeneration of the mammalian digit tip. Cell Stem Cell. 2016;19:433–48.PubMedCrossRef Johnston APW, Yuzwa SA, Carr MJ, Mahmud N, Storer MA, Krause MP, et al. Dedifferentiated Schwann cell precursors secreting paracrine factors are required for regeneration of the mammalian digit tip. Cell Stem Cell. 2016;19:433–48.PubMedCrossRef
110.
Zurück zum Zitat Wu Z, Pu P, Su Z, Zhang X, Nie L, Chang Y. Schwann cell-derived exosomes promote bone regeneration and repair by enhancing the biological activity of porous Ti6Al4V scaffolds. Biochem Biophys Res Commun. 2020;531:559–65.PubMedCrossRef Wu Z, Pu P, Su Z, Zhang X, Nie L, Chang Y. Schwann cell-derived exosomes promote bone regeneration and repair by enhancing the biological activity of porous Ti6Al4V scaffolds. Biochem Biophys Res Commun. 2020;531:559–65.PubMedCrossRef
111.
Zurück zum Zitat Zhang X, Jiang X, Jiang S, Cai X, Yu S, Pei G. Schwann cells promote prevascularization and osteogenesis of tissue-engineered bone via bone marrow mesenchymal stem cell-derived endothelial cells. Stem Cell Res Ther. 2021;12:382.PubMedPubMedCentralCrossRef Zhang X, Jiang X, Jiang S, Cai X, Yu S, Pei G. Schwann cells promote prevascularization and osteogenesis of tissue-engineered bone via bone marrow mesenchymal stem cell-derived endothelial cells. Stem Cell Res Ther. 2021;12:382.PubMedPubMedCentralCrossRef
113.
Zurück zum Zitat Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111:305–17.PubMedCrossRef Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111:305–17.PubMedCrossRef
114.
Zurück zum Zitat Treyball A, Bergeron AC, Brooks DJ, Langlais AL, Hashmi H, Nagano K, et al. Propranolol promotes bone formation and limits resorption through novel mechanisms during anabolic parathyroid hormone treatment in female C57BL/6J mice. J Bone Miner Res. 2022;37:954–71.PubMedCrossRef Treyball A, Bergeron AC, Brooks DJ, Langlais AL, Hashmi H, Nagano K, et al. Propranolol promotes bone formation and limits resorption through novel mechanisms during anabolic parathyroid hormone treatment in female C57BL/6J mice. J Bone Miner Res. 2022;37:954–71.PubMedCrossRef
115.
Zurück zum Zitat Khosla S, Drake MT, Volkman TL, Thicke BS, Achenbach SJ, Atkinson EJ, et al. Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism. J Clin Invest. 2018;128:4832–42.PubMedPubMedCentralCrossRef Khosla S, Drake MT, Volkman TL, Thicke BS, Achenbach SJ, Atkinson EJ, et al. Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism. J Clin Invest. 2018;128:4832–42.PubMedPubMedCentralCrossRef
116.
Zurück zum Zitat Schlienger RG, Kraenzlin ME, Jick SS, Meier CR. Use of beta-blockers and risk of fractures. JAMA. 2004;292:1326–32.PubMedCrossRef Schlienger RG, Kraenzlin ME, Jick SS, Meier CR. Use of beta-blockers and risk of fractures. JAMA. 2004;292:1326–32.PubMedCrossRef
117.
Zurück zum Zitat Turker S, Karatosun V, Gunal I. Beta-blockers increase bone mineral density. Clin Orthop Relat Res. 2006;443:73–4.PubMedCrossRef Turker S, Karatosun V, Gunal I. Beta-blockers increase bone mineral density. Clin Orthop Relat Res. 2006;443:73–4.PubMedCrossRef
118.
Zurück zum Zitat Lary CW, Hinton AC, Nevola KT, Shireman TI, Motyl KJ, Houseknecht KL, et al. Association of beta blocker use with bone mineral density in the Framingham Osteoporosis Study: a cross-sectional study. JBMR PLUS. 2020;4: e10388.PubMedPubMedCentralCrossRef Lary CW, Hinton AC, Nevola KT, Shireman TI, Motyl KJ, Houseknecht KL, et al. Association of beta blocker use with bone mineral density in the Framingham Osteoporosis Study: a cross-sectional study. JBMR PLUS. 2020;4: e10388.PubMedPubMedCentralCrossRef
119.
Zurück zum Zitat Minkowitz B, Boskey AL, Lane JM, Pearlman HS, Vigorita VJ. Effects of propranolol on bone metabolism in the rat. J Orthop Res. 1991;9:869–75.PubMedCrossRef Minkowitz B, Boskey AL, Lane JM, Pearlman HS, Vigorita VJ. Effects of propranolol on bone metabolism in the rat. J Orthop Res. 1991;9:869–75.PubMedCrossRef
121.
Zurück zum Zitat Lee S, Remark LH, Buchalter DB, Josephson AM, Wong MZ, Litwa HP, et al. Propranolol reverses impaired fracture healing response observed with selective serotonin reuptake inhibitor treatment. J Bone Miner Res. 2020;35:932–41.PubMedCrossRef Lee S, Remark LH, Buchalter DB, Josephson AM, Wong MZ, Litwa HP, et al. Propranolol reverses impaired fracture healing response observed with selective serotonin reuptake inhibitor treatment. J Bone Miner Res. 2020;35:932–41.PubMedCrossRef
122.
Zurück zum Zitat Wang L, Zhou S, Liu B, Lei D, Zhao Y, Lu C, et al. Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis. J Orthop Res. 2006;24:2238–45.PubMedCrossRef Wang L, Zhou S, Liu B, Lei D, Zhao Y, Lu C, et al. Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis. J Orthop Res. 2006;24:2238–45.PubMedCrossRef
123.
Zurück zum Zitat Wang L, Cao J, Lei DL, Cheng XB, Zhou HZ, Hou R, et al. Application of nerve growth factor by gel increases formation of bone in mandibular distraction osteogenesis in rabbits. Br J Oral Maxillofac Surg. 2010;48:515–9.PubMedCrossRef Wang L, Cao J, Lei DL, Cheng XB, Zhou HZ, Hou R, et al. Application of nerve growth factor by gel increases formation of bone in mandibular distraction osteogenesis in rabbits. Br J Oral Maxillofac Surg. 2010;48:515–9.PubMedCrossRef
124.
Zurück zum Zitat Yan X-Z, Ge S-H, Sun Q-F, Guo H-M, Yang P-S. A pilot study evaluating the effect of recombinant human bone morphogenetic protein-2 and recombinant human beta-nerve growth factor on the healing ofclass III furcation defects in dogs. J Periodontol. 2010;81:1289–98.PubMedCrossRef Yan X-Z, Ge S-H, Sun Q-F, Guo H-M, Yang P-S. A pilot study evaluating the effect of recombinant human bone morphogenetic protein-2 and recombinant human beta-nerve growth factor on the healing ofclass III furcation defects in dogs. J Periodontol. 2010;81:1289–98.PubMedCrossRef
125.
Zurück zum Zitat Yang S, Cheng J, Man C, Jiang L, Long G, Zhao W, et al. Effects of exogenous nerve growth factor on the expression of BMP-9 and VEGF in the healing of rabbit mandible fracture with local nerve injury. J Orthop Surg Res. 2021;16:74.PubMedPubMedCentralCrossRef Yang S, Cheng J, Man C, Jiang L, Long G, Zhao W, et al. Effects of exogenous nerve growth factor on the expression of BMP-9 and VEGF in the healing of rabbit mandible fracture with local nerve injury. J Orthop Surg Res. 2021;16:74.PubMedPubMedCentralCrossRef
126.
Zurück zum Zitat Rivera KO, Russo F, Boileau RM, Tomlinson RE, Miclau T, Marcucio RS, et al. Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion. Sci Rep. 2020;10:22241.PubMedPubMedCentralCrossRef Rivera KO, Russo F, Boileau RM, Tomlinson RE, Miclau T, Marcucio RS, et al. Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion. Sci Rep. 2020;10:22241.PubMedPubMedCentralCrossRef
127.
Zurück zum Zitat Xu J, Li Z, Tower RJ, Negri S, Wang Y, Meyers CA, et al. NGF-p75 signaling coordinates skeletal cell migration during bone repair. Sci Adv. 2022;8:eabl5716.PubMedPubMedCentralCrossRef Xu J, Li Z, Tower RJ, Negri S, Wang Y, Meyers CA, et al. NGF-p75 signaling coordinates skeletal cell migration during bone repair. Sci Adv. 2022;8:eabl5716.PubMedPubMedCentralCrossRef
128.
Zurück zum Zitat Johnstone MR, Brady RD, Schuijers JA, Church JE, Orr D, Quinn JMW, et al. The selective TrkA agonist, gambogic amide, promotes osteoblastic differentiation and improves fracture healing in mice. J Musculoskelet Neuronal Interact. 2019;19:94–103.PubMedPubMedCentral Johnstone MR, Brady RD, Schuijers JA, Church JE, Orr D, Quinn JMW, et al. The selective TrkA agonist, gambogic amide, promotes osteoblastic differentiation and improves fracture healing in mice. J Musculoskelet Neuronal Interact. 2019;19:94–103.PubMedPubMedCentral
129.
Zurück zum Zitat Takeda K, Shiba H, Mizuno N, Hasegawa N, Mouri Y, Hirachi A, et al. Brain-derived neurotrophic factor enhances periodontal tissue regeneration. Tissue Eng. 2005;11:1618–29.PubMedCrossRef Takeda K, Shiba H, Mizuno N, Hasegawa N, Mouri Y, Hirachi A, et al. Brain-derived neurotrophic factor enhances periodontal tissue regeneration. Tissue Eng. 2005;11:1618–29.PubMedCrossRef
130.
Zurück zum Zitat Takeda K, Sakai N, Shiba H, Nagahara T, Fujita T, Kajiya M, et al. Characteristics of high-molecular-weight hyaluronic acid as a brain-derived neurotrophic factor scaffold in periodontal tissue regeneration. Tissue Eng Part A. 2011;17:955–67.PubMedCrossRef Takeda K, Sakai N, Shiba H, Nagahara T, Fujita T, Kajiya M, et al. Characteristics of high-molecular-weight hyaluronic acid as a brain-derived neurotrophic factor scaffold in periodontal tissue regeneration. Tissue Eng Part A. 2011;17:955–67.PubMedCrossRef
131.
Zurück zum Zitat Li Y, Yang L, He S, Hu J. The effect of semaphorin 3A on fracture healing in osteoporotic rats. J Orthop Sci. 2015;20:1114–21.PubMed Li Y, Yang L, He S, Hu J. The effect of semaphorin 3A on fracture healing in osteoporotic rats. J Orthop Sci. 2015;20:1114–21.PubMed
132.
Zurück zum Zitat Jimbo R, Singer J, Tovar N, Marin C, Neiva R, Bonfante EA, et al. Regeneration of the cementum and periodontal ligament using local BDNF delivery in class II furcation defects. J Biomed Mater Res. 2018;106:1611–7.CrossRef Jimbo R, Singer J, Tovar N, Marin C, Neiva R, Bonfante EA, et al. Regeneration of the cementum and periodontal ligament using local BDNF delivery in class II furcation defects. J Biomed Mater Res. 2018;106:1611–7.CrossRef
133.
Zurück zum Zitat Ramalho I, Bergamo E, Lopes A, Medina-Cintrón C, Neiva R, Witek L, et al. Periodontal tissue regeneration using brain-derived neurotrophic factor delivered by collagen sponge. Tissue Eng Part A. 2019;25:1072–83.PubMedCrossRef Ramalho I, Bergamo E, Lopes A, Medina-Cintrón C, Neiva R, Witek L, et al. Periodontal tissue regeneration using brain-derived neurotrophic factor delivered by collagen sponge. Tissue Eng Part A. 2019;25:1072–83.PubMedCrossRef
134.
Zurück zum Zitat Jimbo R, Tovar N, Janal MN, Mousa R, Marin C, Yoo D, et al. The effect of brain-derived neurotrophic factor on periodontal furcation defects. PLoS ONE. 2014;9: e84845.PubMedPubMedCentralCrossRef Jimbo R, Tovar N, Janal MN, Mousa R, Marin C, Yoo D, et al. The effect of brain-derived neurotrophic factor on periodontal furcation defects. PLoS ONE. 2014;9: e84845.PubMedPubMedCentralCrossRef
135.
Zurück zum Zitat Shi L, Feng L, Zhu M-L, Yang Z-M, Wu T-Y, Xu J, et al. Vasoactive intestinal peptide stimulates bone marrow-mesenchymal stem cells osteogenesis differentiation by activating Wnt/β-catenin signaling pathway and promotes rat skull defect repair. Stem Cells Dev. 2020;29:655–66.PubMedCrossRef Shi L, Feng L, Zhu M-L, Yang Z-M, Wu T-Y, Xu J, et al. Vasoactive intestinal peptide stimulates bone marrow-mesenchymal stem cells osteogenesis differentiation by activating Wnt/β-catenin signaling pathway and promotes rat skull defect repair. Stem Cells Dev. 2020;29:655–66.PubMedCrossRef
136.
Zurück zum Zitat Ma W, Lyu H, Pandya M, Gopinathan G, Luan X, Diekwisch TGH. Successful application of a galanin-coated scaffold for periodontal regeneration. J Dent Res. 2021;100:1144–52.PubMedPubMedCentralCrossRef Ma W, Lyu H, Pandya M, Gopinathan G, Luan X, Diekwisch TGH. Successful application of a galanin-coated scaffold for periodontal regeneration. J Dent Res. 2021;100:1144–52.PubMedPubMedCentralCrossRef
137.
Zurück zum Zitat Koewler NJ, Freeman KT, Buus RJ, Herrera MB, Jimenez-Andrade JM, Ghilardi JR, et al. Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur. J Bone Miner Res. 2007;22:1732–42.PubMedCrossRef Koewler NJ, Freeman KT, Buus RJ, Herrera MB, Jimenez-Andrade JM, Ghilardi JR, et al. Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur. J Bone Miner Res. 2007;22:1732–42.PubMedCrossRef
138.
Zurück zum Zitat Rapp AE, Kroner J, Baur S, Schmid F, Walmsley A, Mottl H, et al. Analgesia via blockade of NGF/TrkA signaling does not influence fracture healing in mice. J Orthop Res. 2015;33:1235–41.PubMedCrossRef Rapp AE, Kroner J, Baur S, Schmid F, Walmsley A, Mottl H, et al. Analgesia via blockade of NGF/TrkA signaling does not influence fracture healing in mice. J Orthop Res. 2015;33:1235–41.PubMedCrossRef
139.
Zurück zum Zitat Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: from regeneration to cancer. Cancer Cell. 2017;31:342–54.PubMedCrossRef Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: from regeneration to cancer. Cancer Cell. 2017;31:342–54.PubMedCrossRef
140.
Zurück zum Zitat Demir IE, Tieftrunk E, Schorn S, Friess H, Ceyhan GO. Nerve growth factor & TrkA as novel therapeutic targets in cancer. Biochim Biophys Acta. 2016;1866:37–50.PubMed Demir IE, Tieftrunk E, Schorn S, Friess H, Ceyhan GO. Nerve growth factor & TrkA as novel therapeutic targets in cancer. Biochim Biophys Acta. 2016;1866:37–50.PubMed
142.
Zurück zum Zitat Desai AV, Robinson GW, Gauvain K, Basu EM, Macy ME, Maese L, et al. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. 2022;24:1776–89.PubMedPubMedCentralCrossRef Desai AV, Robinson GW, Gauvain K, Basu EM, Macy ME, Maese L, et al. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro Oncol. 2022;24:1776–89.PubMedPubMedCentralCrossRef
Metadaten
Titel
Role of the Peripheral Nervous System in Skeletal Development and Regeneration: Controversies and Clinical Implications
verfasst von
Mohamed G. Hassan
Allison L. Horenberg
Ariella Coler-Reilly
Warren L. Grayson
Erica L. Scheller
Publikationsdatum
14.08.2023
Verlag
Springer US
Erschienen in
Current Osteoporosis Reports / Ausgabe 5/2023
Print ISSN: 1544-1873
Elektronische ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-023-00815-5

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