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

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.