Journal
CELL REPORTS
Volume 31, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.107696
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Funding
- National Institute of Dental and Craniofacial Research (NIDCR) [R21 DE027922]
- NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [R01 AR070773, K08 AR068316]
- NIH/NIDCR [R21 DE027922]
- U.S. Department of Defense (U.S. Army Medical Research Acquisition Activity [USAMRAA]) [W81XWH-18-1-0336, W81XWH-18-1-0121, W81XWH-18-10613]
- American Cancer Society (Research Scholar Grant) [RSG-18-027-01-CSM]
- Maryland Stem Cell Research Foundation
- Musculoskeletal Transplant Foundation
- NIH/NIAMS [R01 AR068934]
- U.S. Department of Veterans Affairs (VA) Merit Award [I01BX001234]
- [IK6BX004984]
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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-1 beta/TNF-alpha-rich defect niche, with consequent axonal ingrowth. In calvarial osteoblasts, IL-1 beta and TNF-alpha stimulate Ngf and downstream NF-kappa B 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.
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