内质网钙通道TMCO1在模拟失重导致软骨功能变化中的作用及机制研究

Changes in mechanical load acting on cartilage can regulate chondrocyte metabolic activity, and long-term space flight causes degeneration of cartilage function. Studies have shown that the ability of chondrocytes to secrete extracellular matrix is significantly reduced under weightlessness, leading to cartilage degeneration and adversely affecting astronauts' health. A variety of factors can stimulate the alteration of intracellular calcium signaling, thereby regulating cell proliferation, apoptosis and matrix secretion. In the weightless state, calcium signal-mediated mechanical signaling and its biological function in chondrocytes under weightlessness are still unclear. TMCO1 is a newly discovered endoplasmic reticulum calcium channel protein, which can participate in the regulation of calcium homeostasis, cancer and follicular development, but its effect on cartilage function has not been reported. Our previous study found that TMCO1 expression was reduced in the cartilage tissue of hindlimb unloading simulated weightlessness, and the loss of TMCO1 caused a significant up-regulation of hypertrophic chondrocyte markers and a thinning of the articular cartilage surface. In this project, we further explored the expression characteristics of TMCO1 in cartilage differentiation and its mechanism of action on cartilage function, and used TMCO1 gene modified mice to explore the role of TMCO1 in the change of cartilage function caused by simulated microgravity. This study will provide new targets for the protection against cartilage loss caused by weightlessness.

作用于软骨上的力学负荷变化能够调节软骨细胞代谢活动，长期航天飞行会导致软骨功能退化。已有研究显示，失重状态下软骨细胞分泌胞外基质能力显著降低，导致软骨功能退变，对航天员身体健康造成不利影响。多种因素能够刺激软骨细胞内钙信号变化，进而调控细胞增殖、凋亡和基质的分泌。失重状态下软骨细胞胞内钙介导的力学信号传导及其生物学功能，目前尚不明确。TMCO1是新发现的一种内质网钙通道蛋白，能够参与细胞钙稳态调控、癌症发生、卵泡发育等，但其对软骨功能的调控未见报道。我们前期研究发现，在尾吊模拟失重的软骨组织中TMCO1表达降低，TMCO1缺失能够引起肥大软骨细胞标志物明显上调，关节软骨表层变薄。本项目进一步深入探讨TMCO1在软骨向分化过程中的表达变化特征及其对软骨功能调控的作用机制，并利用TMCO1基因修饰小鼠探究TMCO1在模拟失重引起软骨功能变化中的作用，为失重导致软骨功能退化的对抗防护提供新靶点。

作用于软骨上的力学负荷变化能够调节软骨细胞代谢活动，长期航天飞行会导致软骨功能退化。TMCO1是存在于细胞内质网上的钙通道蛋白，在调控细胞钙稳态过程中发挥重要作用。航天失重环境下细胞内钙平衡被打破，通过钙通道蛋白介导的胞内钙信号发生变化进而影响细胞代谢正常进行。我们研究发现，TMCO1能够促进软骨细胞分化，有助于维持软骨细胞分泌胞外基质的能力；TMCO1缺失引起软骨细胞内质网钙增加及钙相关信号通路变化，TMCO1过表达能够回补TMCO1缺失导致的软骨功能降低；回转模拟失重及4G超重抑制软骨细胞功能；尾吊28天模拟失重模型中，小鼠关节软骨形态结构发生微弱变化，但正常功能并没有受到影响；TMCO1缺失抑制软骨细胞功能及成年小鼠关节软骨功能，而在老年性骨关节炎发生发展中，TMCO1的缺失能够显著抑制骨关节炎的进程，保护骨关节形态结构完整。综上，TMCO1在维持软骨细胞功能中发挥重要作用，并且TMCO1在幼年小鼠骨组织生长发育及老年性骨关节炎进展中发挥不同功能，该研究为力负荷状态下软骨功能的变化及骨关节炎疾病的治疗提供理论基础。