State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Cell Signal. 2023 Sep;109:110779. doi: 10.1016/j.cellsig.2023.110779. Epub 2023 Jun 17.
Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed on sensory neurons where it serves as a polymodal receptor for detecting physical and chemical stimuli. However, the role of TRPV1 in bone metabolism remains largely unclear. This study aimed to investigate the underlying mechanism of neuronal TRPV1 in regulating bone defect repair. In vivo experiment verified that TRPV1 activation could trigger dorsal root ganglion (DRG) producing the neuropeptide calcitonin gene-related peptide (CGRP) in mice. The accelerated bone healing of femoral defect in this process was observed compared to the control group (p < 0.05). Conversely, Trpv1 knockdown led to reduced CGRP expression in DRG and nerves innervating femur bone tissue, following impaired bone formation and osteogenic capability in the defect region (p < 0.05), which could be rescued by local CGRP treatment. In vitro, results revealed that TRPV1 function in DRG neurons contributed essentially to the regulation of osteoblast physiology through affecting the production and secretion of CGRP. The capsaicin-activated neuronal TRPV1-CGRP axis could enhance the proliferation, migration and differentiation of osteoblasts (p < 0.05). Furthermore, we found that the promoting role of neuronal TRPV1 in osteogenesis was associated with Hippo signaling pathway, reflected by the phosphorylation protein level of large tumor suppressor 1 (LATS1), MOB kinase activator 1 (MOB1) and Yes-associated protein (YAP), as well as the subcellular location of YAP. Our study clarified the effects and intrinsic mechanisms of neuronal TRPV1 on bone defect repair, which might offer us a therapeutic implication for bone disorders.
瞬时受体电位香草酸型 1（TRPV1）在感觉神经元上高度表达，作为一种多模式受体，用于检测物理和化学刺激。然而，TRPV1 在骨代谢中的作用在很大程度上仍不清楚。本研究旨在探讨神经元 TRPV1 在调节骨缺损修复中的潜在机制。体内实验验证了 TRPV1 的激活可以触发背根神经节（DRG）产生降钙素基因相关肽（CGRP）在小鼠中。与对照组相比，观察到该过程中股骨缺损处的骨愈合加速（p<0.05）。相反，Trpv1 敲低导致 DRG 和支配股骨组织神经中的 CGRP 表达减少，随后在缺陷区域骨形成和成骨能力受损（p<0.05），局部 CGRP 处理可挽救这种情况。在体外，结果表明，DRG 神经元中 TRPV1 的功能通过影响 CGRP 的产生和分泌，对成骨细胞的生理学起到了重要的调节作用。辣椒素激活的神经元 TRPV1-CGRP 轴可以增强成骨细胞的增殖、迁移和分化（p<0.05）。此外，我们发现神经元 TRPV1 对成骨作用的促进作用与 Hippo 信号通路有关，反映在大肿瘤抑制因子 1（LATS1）、MOB 激酶激活物 1（MOB1）和 Yes 相关蛋白（YAP）的磷酸化蛋白水平以及 YAP 的亚细胞定位上。本研究阐明了神经元 TRPV1 对骨缺损修复的影响及其内在机制，这可能为骨疾病的治疗提供了一种新的思路。
