Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710.
Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1316-21. doi: 10.1073/pnas.1319569111. Epub 2014 Jan 13.
Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharmacologic therapies for joint diseases. Transient receptor potential vanilloid 4 (TRPV4), a Ca(2+)-permeable osmomechano-TRP channel, is highly expressed in articular chondrocytes, and loss of TRPV4 function is associated with joint arthropathy and osteoarthritis. The goal of this study was to examine the hypothesis that TRPV4 transduces dynamic compressive loading in articular chondrocytes. We first confirmed the presence of physically induced, TRPV4-dependent intracellular Ca(2+) signaling in agarose-embedded chondrocytes, and then used this model system to study the role of TRPV4 in regulating the response of chondrocytes to dynamic compression. Inhibition of TRPV4 during dynamic loading prevented acute, mechanically mediated regulation of proanabolic and anticatabolic genes, and furthermore, blocked the loading-induced enhancement of matrix accumulation and mechanical properties. Furthermore, chemical activation of TRPV4 by the agonist GSK1016790A in the absence of mechanical loading similarly enhanced anabolic and suppressed catabolic gene expression, and potently increased matrix biosynthesis and construct mechanical properties. These findings support the hypothesis that TRPV4-mediated Ca(2+) signaling plays a central role in the transduction of mechanical signals to support cartilage extracellular matrix maintenance and joint health. Moreover, these insights raise the possibility of therapeutically targeting TRPV4-mediated mechanotransduction for the treatment of diseases such as osteoarthritis, as well as to enhance matrix formation and functional properties of tissue-engineered cartilage as an alternative to bioreactor-based mechanical stimulation.
关节的机械负荷对于维持关节软骨的健康和功能至关重要。虽然软骨细胞的机械转导机制尚未完全阐明，但它可能为关节疾病的新物理或药物治疗提供重要的见解。瞬时受体电位香草酸 4 型（TRPV4）是一种 Ca2+通透性的渗透压机械 TRP 通道，在关节软骨细胞中高度表达，TRPV4 功能丧失与关节关节炎和骨关节炎有关。本研究的目的是检验 TRPV4 在关节软骨细胞中传递动态压缩负荷的假说。我们首先证实了琼脂糖包埋软骨细胞中存在物理诱导的、依赖 TRPV4 的细胞内 Ca2+信号，然后使用该模型系统研究 TRPV4 在调节软骨细胞对动态压缩的反应中的作用。在动态加载过程中抑制 TRPV4 可防止机械介导的急性促合成代谢和抗分解代谢基因的调节，此外，还阻止了加载诱导的基质积累和机械性能的增强。此外，激动剂 GSK1016790A 化学激活 TRPV4 在没有机械加载的情况下同样增强了合成代谢和抑制了分解代谢基因的表达，并显著增加了基质生物合成和构建的机械性能。这些发现支持了 TRPV4 介导的 Ca2+信号在传递机械信号以支持软骨细胞外基质维持和关节健康方面发挥核心作用的假说。此外，这些发现提出了通过靶向 TRPV4 介导的机械转导来治疗骨关节炎等疾病的可能性，以及通过生物反应器为基础的机械刺激来增强组织工程软骨的基质形成和功能特性。
