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

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.

Spatial histomorphometry reveals that local peripheral nerves modulate but are not required for skeletal adaptation to applied load in mice

“…Though our data and others show that local nerves are not necessary for this response, it remains possible that changes in nerve function are sufficient to modulate the amount of bone formed. This could be through the hypersecretion of local neurotransmitters or through secondary changes in nervous system function throughout the body (7) . Nerve growth factor (NGF) is one of the most highly and consistently upregulated genes in bone after compressive loading of the limbs (16,37,38) .…”

“…In addition, RadialQuant of periosteal axon density showed a trending interaction effect of load and radial bin (2-way ANOVA, p=0.087), indicating possible spatial redistribution or mild sprouting of axons following mechanical loading. In addition to effects on nerves, NGF can activate TrkA receptors on endothelial cells and potentially also osteolineage cells to regulate do novo vasculogenesis and bone formation directly (7,39) . Consistent with this, recent work found that when the high-affinity NGF receptor TrkA was blocked globally throughout the body, this prevented 41% of the load-induced increase in BFR, 16% of the load-induced increase in mineralizing osteoblasts, and 31% of load-induced increase in osteoblast activity (16) .…”

“…A global role for prostaglandin signaling in sensory nerves in the anabolic response to load has also been reported (17) . Overall, when isolating the interactions between nerves and bone it remains important to consider the broad distribution of the nervous system throughout the body, the potential for secretion of neurotransmitters by non-neural cells, and the fact that most nerve-derived signals are also carried throughout the circulation (1,7) .…”

“…Nerves in bone also have potential to release neurotransmitters near bone cells to modulate skeletal metabolism (1) . Assessment of diverse studies over the past 100years reveals that local nerves in and around bone (specifically) are likely to have neutral or mild modulatory functions on bone health in vivo, rather than an absolute requirement that links bone health to nerve function (7) . Clinically, when peripheral nerve damage or dysfunction extends to other body systems, this has been associated with increased skeletal fragility in contexts of diabetes, spinal cord injury, chemotherapyinduced osteoporosis, multiple sclerosis, and anorexia (8)(9)(10)(11)(12)(13) .…”

Sarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy

“…This is in line with recent studies that have highlighted the potential relevance of neuroskeletal function to bone health in settings of development, homeostasis, and regeneration (reviewed in refs. 14,15). Together, this has prompted the hypothesis that neural dysfunction, through the onset of DPN, may be responsible for the onset and progression of diabetic skeletal disease -representing a possible unified target point for treatment of both disorders.…”