Impact of the Sympathetic Nervous System on Fracture Healing
Studies have reliably demonstrated that the sympathetic nervous system (SNS) innervates bone and that adrenergic receptors are present on both osteoblasts and osteoclasts [
111‐
113]. Although additional research is still needed, the aggregate of the findings so far suggests that while local sympathetic denervation improves fracture healing, complete knockout of the SNS impairs fracture healing.
Experiments dating back to the mid-twentieth century have supported the idea that local sympathectomy increases blood flow to damaged tissues, potentially resulting in an increase in bone growth and an acceleration of fracture healing [
114,
115]. For example, when these experimenters fractured the hind legs of 12 dogs after performing a lumbosacral sympathectomy on them, they determined that there was a marked enhancement of the healing in 11 of the cases [
115]. More recent experiments have provided support for this idea. When the mandible of rats was fractured and a bone-borne distractor implanted to induce distraction osteogenesis (DO), rats who had simultaneously experienced a cervical sympathetic trunk transection exhibited increased bone mineral density and more continuous bone formation at 14 days when compared to those rats with intact cervical sympathetic trunks [
116].
Building on this experiment, researchers again used a rat model of mandibular DO with a simultaneous cervical sympathetic trunk transection to better understand the influence of the SNS on mesenchymal stem cells (MSCs) [
117]. Immunohistochemical staining for nestin, a marker for MSCs, demonstrated an increased number of MSCs in bone-forming areas in the sympathetically denervated rats when compared with controls whose MSCs largely remained within their perivascular stem cell niche. It was also shown that norepinephrine, the primary neurotransmitter released by the SNS, prevented the osteogenic differentiation of MSCs, while downregulation of the β3-adrenergic receptor (
ardb3) mitigated this norepinephrine-dependent inhibition of differentiation [
117]. Taken together, these results show that the SNS decreases the migration and differentiation of MSCs, suggesting again that the intact SNS may exert an inhibitory control on bone growth and healing.
Additional support for the idea that inhibition of the SNS improves fracture healing comes from studies that manipulated the interaction between sensory and sympathetic nerves. Prostaglandin E2, a known mediator of pain, is secreted by osteoblasts when bone density decreases [
118••]. Evidence suggests that this substance acts on EP4 receptors present on primary afferent sensory nerve fibers to inhibit sympathetic tone and via this pathway stimulate an increase in bone density. Likely due to the inhibitory effect of sympathetic signaling on MSC activity, EP4 receptor knockout mice displayed decreased MSC differentiation to osteoblasts and diminished osteogenesis [
119].
On the other hand, there is a growing amount of research insinuating that total elimination of the SNS diminishes aspects of fracture healing. Our understanding of the effects of total sympathectomy has been greatly enhanced through the strategic use of neurotoxins like 6-hydroxydopamine (6-OHDA) [
17,
120]. This potent compound is known for its deleterious impact on peripheral sympathetic nerve fibers, culminating in the interrupted production of norepinephrine [
17,
120]. For example, upon injecting 6-OHDA into a mouse model, the measured amount of mineralized bone was decreased and the structural integrity of bones was compromised in the time period following femoral fractures, thereby underlining the crucial role of the SNS in optimal bone recovery post-trauma [
120]. Further, in a second study that examined the femoral fracture healing trajectory in mice devoid of sympathetic innervation due to 6-OHDA application, mice displayed decreased bone stability and a pronounced delay in bony callus development [
17]. This provides additional evidence for the integral role of the SNS during bone repair. However, it is important to note that pharmacological drugs, like 6-OHDA, that were used in these studies may have poorly characterized impacts on the bone microenvironment that could also impact these results [
121].
Finally, the SNS’s function may extend to pain modulation during fracture healing [
7]. Following a fracture, several neurotransmitters, cytokines, and growth factors are released which cause the proliferation of new sympathetic fibers that augment the perception of pain during the healing trajectory [
50,
122]. However, while some experiments have found evidence for a heightened threshold for touch sensitivity after fracture in completely sympathectomized mice, another experiment concluded that mice treated with 6-OHDA displayed no difference in withdrawal thresholds [
7,
17,
123]. In light of these research findings, the role of the SNS in fracture healing is revealed as profoundly complex, encompassing not only the physical repair process but also potentially the modulation of pain perception.
The Impact of Stress and Sympathetic Nervous System Activation on Fracture Healing
Chronic stress and its resultant chronic activation of the SNS are recognized as potential hindrances to the healing process [
124,
125,
126••,
127]. Through the continuous release of norepinephrine, chronic stress induces a dysregulation of immune responses that can deleteriously affect fracture healing [
126••,
128,
129]. Chronic stress can be induced in mice via the chronic subordinate colony housing paradigm, in which male mice are continuously exposed to a dominant male aggressor. In mice with fractures who are experiencing chronic stress, researchers have demonstrated reduced neoangiogenesis at the fracture site, decreased rates of chondrocyte-to-osteoblast transdifferentiation, and poor functional fracture healing outcomes when compared to controls [
126••]. Additional evidence exists for the idea that chronic stress impairs endochondral ossification [
127]. Further, an imbalanced immune response to fractures, characterized by increased neutrophils and decreased lymphocytes at the fracture site, was shown to be mediated by adrenergic signaling in chronically stressed mice [
126••].
Chronic stress is also known to influence pain perception and may theoretically exacerbate pain experiences associated with fractures [
130‐
132]. This has significant implications for patient comfort and recovery, particularly in instances of complex or slow-healing fractures. In the case of complex regional pain syndrome, lumbar sympathetic blocks have beneficial impacts on pain and functionality, suggesting a potential area for investigation for the treatment of chronic stress-induced pain in fracture patients [
133,
134]. Further research is necessary to elucidate the relationship between the SNS, chronic stress, and fracture healing more comprehensively, particularly with regard to how chronic stress affects the nervous system’s involvement in the various stages of fracture healing. Understanding these interactions may lead to the development of more effective therapeutic strategies for fracture healing, potentially by targeting the SNS or stress response directly.