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

doi:10.1016/j.celrep.2020.107696

A Neurotrophic Mechanism Directs Sensory Nerve Transit in Cranial Bone

Cell Rep. 2020 May 26;31(8):107696. doi: 10.1016/j.celrep.2020.107696.

Authors

Affiliations

¹ Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA.
² Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Orthopaedics and Traumatology, University of Verona, 37129 Verona, Italy.
³ Department of Orthopaedics, Johns Hopkins University, Baltimore, MD 21205, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
⁴ Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK.
⁵ Department of Orthopaedics, Johns Hopkins University, Baltimore, MD 21205, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA. Electronic address: tclemen5@jhmi.edu.
⁶ Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: awjames@jhmi.edu.

Abstract

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.

Keywords: NGF; TrkA; bone healing; calvarial bone; osteogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bone Remodeling / genetics*
Bone and Bones / injuries*
Disease Models, Animal
Mice
Skull / innervation*

Abstract

Publication types

MeSH terms

Grants and funding