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

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


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Mice
  • Mice, Mutant Strains
  • Muscle, Skeletal / metabolism*
  • Nerve Growth Factor / genetics
  • Nerve Growth Factor / metabolism*
  • Osteoblasts / metabolism
  • Osteogenesis / physiology*
  • Receptor, trkA / genetics
  • Receptor, trkA / metabolism*
  • Sensory Receptor Cells / metabolism*
  • Weight-Bearing / physiology
  • Wnt Signaling Pathway / physiology*


  • Nerve Growth Factor
  • Receptor, trkA