Bone is richly innervated by nerve growth factor–responsive (NGF-responsive) tropomyosin receptor kinase A–expressing (TrKa-expressing) sensory nerve fibers, which are required for osteochondral progenitor expansion during mammalian skeletal development. Aside from pain sensation, little is known regarding the role of sensory innervation in bone repair. Here, we characterized the reinnervation of tissue following experimental ulnar stress fracture and assessed the impact of loss of TrkA signaling in this process. Sequential histological data obtained in reporter mice subjected to fracture demonstrated a marked upregulation of NGF expression in periosteal stromal progenitors and fracture-associated macrophages. Sprouting and arborization of CGRP+TrkA+ sensory nerve fibers within the reactive periosteum in NGF-enriched cellular domains were evident at time points preceding periosteal vascularization, ossification, and mineralization. Temporal inhibition of TrkA catalytic activity by administration of 1NMPP1 to TrkAF592A mice significantly reduced the numbers of sensory fibers, blunted revascularization, and delayed ossification of the fracture callus. We observed similar deficiencies in nerve regrowth and fracture healing in a mouse model of peripheral neuropathy induced by paclitaxel treatment. Together, our studies demonstrate an essential role of TrkA signaling for stress fracture repair and implicate skeletal sensory nerves as an important upstream mediator of this repair process.
Zhu Li, Carolyn A. Meyers, Leslie Chang, Seungyong Lee, Zhi Li, Ryan Tomlinson, Ahmet Hoke, Thomas L. Clemens, Aaron W. James
Usage data is cumulative from October 2019 through December 2019.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.