Function of peripheral nerves in the development and healing of tendon and bone

Abstract

Although the functions of the peripheral nervous system in whole body homeostasis and sensation have been understood for many years, recent investigation has uncovered new roles for innervation in the musculoskeletal system. This review centers on advances regarding the function of nerves in the development and repair of two connected tissues: tendon and bone. Innervation in healthy tendons is generally confined to the tendon sheaths, and tendon-bone attachment units are typically aneural. In contrast to tendon, bone is an innervated and vascularized structure. Historically, the function of abundant peripheral nerves in bone has been limited to pain and some non-painful sensory perception in disease and injury. Indeed, much of our understanding of peripheral nerves in tendons, bones, and entheses is limited to the source and type of innervation in healthy and injured tissues. However, more recent studies have made important observations regarding the appearance, type, and innervation patterns of nerves during embryonic and postnatal development and in response to injury, which suggest a more expansive role for peripheral nerves in the formation of musculoskeletal tissues. Indeed, tendons and bones develop in a close spatiotemporal relationship in the embryonic mesoderm. Models of limb denervation have shed light on the importance of sensory innervation in bone and to a lesser extent, tendon development, and more recent work has unraveled key nerve signaling pathways. Furthermore, loss of sensory innervation also impairs healing of bone fractures and may contribute to chronic tendinopathy. However, more study is required to translate our knowledge of peripheral nerves to therapeutic strategies to combat bone and tendon diseases.

Keywords: Bone; Innervation; Nerve; Neurotransmitter; Tendon.

Figure 1:. Nerves in development.

At E14.5 in the mouse embryo, TrkA+ sensory fibers are first visible in the perichondrium of long bones and may be found in close vicinity of early tendon primordia (A). At E21, abundant GAP43+ and PGP9.5+ nerves are closely associated with peripheral arteries near the POC (B). P3 marks the early ingrowth of CGRP+ sensory nerves from the periosteum into the POC (C). At P6, the first NPY+ sympathetic nerves can be visualized in the bone marrow (D).

Figure 2:. Nerves in tendon healing.

Acute injury results in hemorrhaging and edema (A). Inflammation is marked by the extension of GAP43+ axons from the paratenon to the tendon proper (B). In the proliferative phase, nerve fiber density in the tendon increases and CGRP+ nerve axons are closely associated with vessels (C). The final phase of remodeling is associated with decreases in nerve density in the proper tendon to restore native neuronal networks (D). Tendons heal with scar.

Fig. 3:. Nerves in fracture healing.

Fracture results in the disruption and bleeding of local vessels which is marked by a hematoma (A). In the inflammatory phase, CGRP+ sensory and TH+ sympathetic nerves first innervate the callus from the periosteum (B). In the fibrovascular phase, nerve density increases in the callus, and nerves are closely associated with ingrowing vessels (C). Bone formation is characterized by a soft cartilage callus at the injury site and marked reductions in nerve density (D). Bone is remodeled to its native structure and strength.