Tomlinson Ryan E, Li Zhi, Li Zhu, Minichiello Liliana, Riddle Ryan C, Venkatesan Arun, Clemens Thomas L
Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287.
Department of Pharmacology, Oxford University, Oxford, OX1 3QT, United Kingdom.
Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3632-E3641. doi: 10.1073/pnas.1701054114. Epub 2017 Apr 17.
Sensory nerves emanating from the dorsal root extensively innervate the surfaces of mammalian bone, a privileged location for the regulation of biomechanical signaling. Here, we show that NGF-TrkA signaling in skeletal sensory nerves is an early response to mechanical loading of bone and is required to achieve maximal load-induced bone formation. First, the elimination of TrkA signaling in mice harboring mutant TrkA alleles was found to greatly attenuate load-induced bone formation induced by axial forelimb compression. Next, both in vivo mechanical loading and in vitro mechanical stretch were shown to induce the profound up-regulation of NGF in osteoblasts within 1 h of loading. Furthermore, inhibition of TrkA signaling following axial forelimb compression was observed to reduce measures of Wnt/β-catenin activity in osteocytes in the loaded bone. Finally, the administration of exogenous NGF to wild-type mice was found to significantly increase load-induced bone formation and Wnt/β-catenin activity in osteocytes. In summary, these findings demonstrate that communication between osteoblasts and sensory nerves through NGF-TrkA signaling is essential for load-induced bone formation in mice.
源自背根的感觉神经广泛支配哺乳动物骨骼表面，这是调节生物力学信号的特殊位置。在此，我们表明骨骼感觉神经中的NGF-TrkA信号传导是对骨骼机械负荷的早期反应，并且是实现最大负荷诱导的骨形成所必需的。首先，发现消除携带突变TrkA等位基因的小鼠中的TrkA信号传导会大大减弱由轴向肢体压缩诱导的负荷诱导的骨形成。其次，体内机械负荷和体外机械拉伸均显示在负荷后1小时内诱导成骨细胞中NGF的显著上调。此外，观察到轴向肢体压缩后TrkA信号传导的抑制会降低负荷骨骼中骨细胞中Wnt/β-连环蛋白活性的指标。最后，发现向野生型小鼠施用外源性NGF会显著增加负荷诱导的骨形成以及骨细胞中Wnt/β-连环蛋白活性。总之，这些发现表明成骨细胞与感觉神经之间通过NGF-TrkA信号传导的通讯对于小鼠负荷诱导的骨形成至关重要。
