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Review
. 2024 Aug 21;39(8):1045-1060.
doi: 10.1093/jbmr/zjae087.

Neuronal regulation of bone and tendon injury repair: a focused review

Mingxin Xu  1 , Manyu Zhu  1 , Qizhi Qin  1 , Xin Xing  1 , Mary Archer  1 , Sowmya Ramesh  1 , Masnsen Cherief  1 , Zhao Li  1 , Benjamin Levi  2 , Thomas L Clemens  3   4 , Aaron W James  1
Affiliations
Review

Neuronal regulation of bone and tendon injury repair: a focused review

Mingxin Xu et al. J Bone Miner Res. .

Abstract

Beyond the sensation of pain, peripheral nerves have been shown to play crucial roles in tissue regeneration and repair. As a highly innervated organ, bone can recover from injury without scar formation, making it an interesting model in which to study the role of nerves in tissue regeneration. As a comparison, tendon is a musculoskeletal tissue that is hypo-innervated, with repair often resulting in scar formation. Here, we reviewed the significance of innervation in 3 stages of injury repair (inflammatory, reparative, and remodeling) in 2 commonly injured musculoskeletal tissues: bone and tendon. Based on this focused review, we conclude that peripheral innervation is essential for phases of proper bone and tendon repair, and that nerves may dynamically regulate the repair process through interactions with the injury microenvironment via a variety of neuropeptides or neurotransmitters. A deeper understanding of neuronal regulation of musculoskeletal repair, and the crosstalk between nerves and the musculoskeletal system, will enable the development of future therapies for tissue healing.

Keywords: bone injury; peripheral nervous system; tendon injury; tissue repair and regeneration.

Plain language summary

Accumulating evidence has shown that, across organs systems, peripheral nerves regulate the process of tissue repair and regeneration. This is particularly relevant in the context of musculoskeletal injuries such as those affecting the bone and tendon. The question then arises: what is the function of peripheral innervation in the repair of bone and tendon injuries? This review offers an in-depth look at the ways in which nerves regulate the healing of bone and tendon injuries at various stages of recovery. A deeper comprehension of the influence of nerves on the repair of these tissues could pave the way for the development of future therapeutic strategies for tissue healing.

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Conflict of interest statement

A.W.J. is scientific advisory board chairman for Novadip LLC, consultant for Lifesprout LLC and Novadip LLC, and Editorial Board of Bone Research, Stem Cells, and The American Journal of Pathology. All the other authors declare no potential conflicts of interest. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

Figures

Figure 1
Figure 1
Neural regulation of fracture repair. Sensory and sympathetic nerves are differentially distributed during the 3 corresponding phases of fracture healing. Callus innervation appears from inflammatory phase, peaks during reparative phase, and retracts during remodeling phase. Cells (macrophages, neutrophils, skeletal progenitor cells, osteoblasts, chondrocytes, osteoclasts) have been identified as targets of sensory and sympathetic nerve-derived neuropeptides during bone healing. Created with BioRender.com.
Figure 2
Figure 2
Key mediators of neural regulation of bone and tendon repair. In bone, during the inflammatory phase, CGRP and SP from sensory neurons target neutrophils and macrophages to enhance inflammation. CGRP and SNS may also affect macrophage polarization. During the reparative phase, CGRP and SP act on osteoblast lineage to promote osteogenesis. Along with NE and NPY from sympathetic nerves, they may also promote angiogenesis by acting on endothelial cells. During the remodeling phase, SP and SNS act on osteoclasts to increase bone resorption, while CGRP decreases osteoclast activities. In tendon, there’s relatively less direct evidence of key mediators on tendon repair. CGRP and SP increase during inflammatory and reparative phase and decrease during remodeling phase, in contrast to SNS-derived mediators such as NPY and VIP. Their potential target cells are listed.
Figure 3
Figure 3
Neural regulation of tendon repair. Sensory and sympathetic nerve supply emerges during the inflammatory phase of tendon healing, reaches its highest level in the reparative phase, and diminishes during the remodeling phase. During this healing process, cells such as macrophages, neutrophils, fibroblasts, and tenocytes may be influenced by neuropeptides released from sensory and sympathetic nerves. Created with BioRender.com.
See this image and copyright information in PMC

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