A Neurotrophic Mechanism Directs Sensory Nerve Transit in Cranial Bone

Carolyn A. Meyers, Seungyong Lee, Takashi Sono, Jiajia Xu, Stefano Negri, Ye Tian, Yiyun Wang, Zhu Li, Sarah Miller, Leslie Chang, Yongxing Gao, Liliana Minichiello, Thomas L. Clemens, Aaron W. James

Research output: Contribution to journalArticlepeer-review


The flat bones of the skull are densely innervated during development, but little is known regarding their role during repair. We describe a neurotrophic mechanism that directs sensory nerve transit in the mouse calvaria. Patent cranial suture mesenchyme represents an NGF (nerve growth factor)-rich domain, in which sensory nerves transit. Experimental calvarial injury upregulates Ngf in an IL-1β/TNF-α-rich defect niche, with consequent axonal ingrowth. In calvarial osteoblasts, IL-1β and TNF-α stimulate Ngf and downstream NF-κB signaling. Locoregional deletion of Ngf delays defect site re-innervation and blunted repair. Genetic disruption of Ngf among LysM-expressing macrophages phenocopies these observations, whereas conditional knockout of Ngf among Pdgfra-expressing cells does not. Finally, inhibition of TrkA catalytic activity similarly delays re-innervation and repair. These results demonstrate an essential role of NGF-TrkA signaling in bone healing and implicate macrophage-derived NGF-induced ingrowth of skeletal sensory nerves as an important mediator of this repair.

Original languageEnglish (US)
Article number107696
JournalCell Reports
Issue number8
StatePublished - May 26 2020


  • NGF
  • TrkA
  • bone healing
  • calvarial bone
  • osteogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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