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
Affiliations
Carolyn A. Meyers
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Seungyong Lee
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Takashi Sono
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Jiajia Xu
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Stefano Negri
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Orthopaedics and Traumatology, University of Verona, 37129 Verona, Italy
Ye Tian
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Yiyun Wang
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Zhu Li
Department of Orthopaedics, Johns Hopkins University, Baltimore, MD 21205, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA
Sarah Miller
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Leslie Chang
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Yongxing Gao
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Liliana Minichiello
Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK
Thomas L. Clemens
Department of Orthopaedics, Johns Hopkins University, Baltimore, MD 21205, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA; Corresponding author and
Aaron W. James
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA; Corresponding author
Summary: 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.
