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Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3632-E3641. doi: 10.1073/pnas.1701054114. Epub 2017 Apr 17.

NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice.

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Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287.
Department of Pharmacology, Oxford University, Oxford, OX1 3QT, United Kingdom.
Baltimore Veterans Administration Medical Center, Baltimore, MD 21201.
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287.
Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287;


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.


Wnt signaling; mechanical loading; nerve growth factor; neurotrophic tyrosine kinase receptor type 1; sensory nerves

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