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Sensory nerves emanating from the dorsal root extensively innervate the surfaces of mammalian bone, a privileged location for the regulation of biomechanical signaling. Here, we show that NGF-TrkA signaling in skeletal sensory nerves is an early response to mechanical loading of bone and is required to achieve maximal load-induced bone formation. First, the elimination of TrkA signaling in mice harboring mutant TrkAF592A alleles was found to greatly attenuate load-induced bone formation induced by axial forelimb compression. Next, both in vivo mechanical loading and in vitro mechanical stretch were shown to induce the profound up-regulation of NGF in osteoblasts within 1 h of loading. Furthermore, inhibition of TrkA signaling following axial forelimb compression was observed to reduce measures of Wnt/β-catenin activity in osteocytes in the loaded bone. Finally, the administration of exogenous NGF to wild-type mice was found to significantly increase load-induced bone formation and Wnt/β-catenin activity in osteocytes. In summary, these findings demonstrate that communication between osteoblasts and sensory nerves through NGF-TrkA signaling is essential for load-induced bone formation in mice.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





E3632 - E3641


Wnt signaling, mechanical loading, nerve growth factor, neurotrophic tyrosine kinase receptor type 1, sensory nerves, Animals, Mice, Mice, Mutant Strains, Muscle, Skeletal, Nerve Growth Factor, Osteoblasts, Osteogenesis, Receptor, trkA, Sensory Receptor Cells, Weight-Bearing, Wnt Signaling Pathway