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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.

Author information

1
Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287.
2
Department of Pharmacology, Oxford University, Oxford, OX1 3QT, United Kingdom.
3
Baltimore Veterans Administration Medical Center, Baltimore, MD 21201.
4
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287.
5
Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287; tclemen5@jhmi.edu.

Abstract

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

PMID:
28416686
PMCID:
PMC5422802
DOI:
10.1073/pnas.1701054114
[Indexed for MEDLINE]
Free PMC Article

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