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

Ryan E. Tomlinson, Zhi Li, Zhu Li, Liliana Minichiello, Ryan C. Riddle, Arun Venkatesan, Thomas L. Clemens

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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 NGFTrkA 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 upregulation 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 loadinduced 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 languageEnglish (US)
Pages (from-to)E3632-E3641
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number18
StatePublished - May 2 2017


  • Mechanical loading
  • Nerve growth factor
  • Neurotrophic tyrosine kinase receptor type 1
  • Sensory nerves
  • Wnt signaling

ASJC Scopus subject areas

  • General


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