Fracture repair requires TrkA signaling by skeletal sensory nerves.
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.
['Li|Zhu|Z|', 'Meyers|Carolyn A|CA|', 'Chang|Leslie|L|', 'Lee|Seungyong|S|', 'Li|Zhi|Z|', 'Tomlinson|Ryan|R|', 'Hoke|Ahmet|A|', 'Clemens|Thomas L|TL|', 'James|Aaron W|AW|']
D000818:Animals D004195:Disease Models, Animal D017102:Fracture Healing D050723:Fractures, Bone D015775:Fractures, Stress D005727:Ganglia, Spinal D017930:Genes, Reporter D021621:Imaging, Three-Dimensional D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D020932:Nerve Growth Factor D010012:Osteogenesis D010521:Periosteum D020917:Receptor, trkA D011984:Sensory Receptor Cells D015398:Signal Transduction D013234:Stem Cells D019076:Transgenes D055114:X-Ray Microtomography
Bone Biology Bone disease