Fracture repair requires TrkA signaling by skeletal sensory nerves
Zhu Li, Carolyn A. Meyers, Leslie Chang, Seungyong Lee, Zhi Li, Ryan Tomlinson, Ahmet Hoke, Thomas L. Clemens, Aaron W. James
Zhu Li, Carolyn A. Meyers, Leslie Chang, Seungyong Lee, Zhi Li, Ryan Tomlinson, Ahmet Hoke, Thomas L. Clemens, Aaron W. James
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Research Article Bone biology

Fracture repair requires TrkA signaling by skeletal sensory nerves

Abstract

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.

Authors

Zhu Li, Carolyn A. Meyers, Leslie Chang, Seungyong Lee, Zhi Li, Ryan Tomlinson, Ahmet Hoke, Thomas L. Clemens, Aaron W. James

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Figure 2

NGF reporter activity after stress fracture.

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NGF reporter activity after stress fracture. (A–U) Representative tile s...
(A–U) Representative tile scans (left), high-magnification images (middle), and representative H&E-stained images (right) of the ulnar fracture site and associated callus in NGF-eGFP reporter animals at serial time points between days 1 and 56 after stress fracture. Reporter activity is shown in green, and nuclear counterstaining is shown in blue. An uninjured control is shown for comparison. The thin dashed white line indicates the uppermost boundary of the periosteum or fracture callus. The thicker dashed white line represents the boundary between the periosteum or fracture callus and the underlying cortical bone. Red arrowheads indicate the fracture site. (V) Semiquantitation of NGF-eGFP reporter activity after fracture on days 1–56 in comparison with the uninjured control. Each dot in the graphs represents a single sample, with the sample numbers indicated below. White scale bars: 50 μm; black scale bars: 20 μm. Data are expressed as the mean ± SD. †P < 0.05 and ††P < 0.01 versus the uninjured control; ##P < 0.01 versus the day-3 time point, by 1-way ANOVA with post hoc Newman-Keuls test.