Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA.
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Orthopaedics and Traumatology, University of Verona, 37129 Verona, Italy.
Cell Rep. 2020 May 26;31(8):107696. doi: 10.1016/j.celrep.2020.107696.
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.
颅骨的扁骨在发育过程中被密集地神经支配,但对于它们在修复过程中的作用知之甚少。我们描述了一种神经营养机制,该机制可引导小鼠颅骨中的感觉神经通过。未闭的颅缝间质代表富含神经生长因子(NGF)的区域,其中感觉神经通过。实验性颅骨损伤可使富含白细胞介素 1β(IL-1β)和肿瘤坏死因子-α(TNF-α)的缺陷龛上调 Ngf,从而导致轴突生长。在颅骨成骨细胞中,IL-1β 和 TNF-α 可刺激 Ngf 和下游 NF-κB 信号转导。Ngf 在 LysM 表达的巨噬细胞中的局部缺失延迟了缺陷部位的再神经支配,并削弱了修复。LysM 表达的巨噬细胞中 Ngf 的基因缺失可模拟这些观察结果,而 Pdgfra 表达细胞中 Ngf 的条件性缺失则不能。最后,TrkA 催化活性的抑制也会延迟再神经支配和修复。这些结果表明 NGF-TrkA 信号在骨愈合中起重要作用,并提示巨噬细胞衍生的 NGF 诱导的骨骼感觉神经生长是这种修复的重要介质。