Introduction
Innervation of the Bone from Development to Regeneration
Coordinated Neural Infiltration Occurs During Skeletal Development
The Skeletal Neural Network Undergoes Active Remodeling During Bone Regeneration and Repair
Neural Contributions to Bone Homeostasis and Regeneration—Positive, Negative, Neutral, or All of the Above?
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%) |