Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60590 Frankfurt am Main, Germany.
Cells. 2021 Oct 9;10(10):2705. doi: 10.3390/cells10102705.
Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction.
机械转导是细胞在感知周围细胞外基质传递的物理力时产生的，导致影响细胞功能的信号事件。这个生理过程是维持关节完整性的前提，而过度负荷是促进关节破坏炎症机制的一个因素。在这里，我们描述了一种来源于炎症关节滑膜的滑膜成纤维细胞 (SF) 的机械转导途径。在强烈上调的去整合素金属蛋白酶 ADAM15 缺失的情况下，该途径的功能完全丧失。机械信号事件涉及 Ca 依赖性激活 c-Jun-N 末端激酶，随后下调长非编码 RNA HOTAIR，并上调代谢能量传感器 Sirtuin-1。ADAM15 通过促进组成性循环机械敏感瞬时受体电位香草素 4 钙通道的细胞膜密度来促进该途径的传入环路。此外，ADAM15 增强了Src 介导的 Pannexin-1 通道的激活，这对于增强 ATP 的释放是必需的，ATP 是嘌呤炎症的介质，在 Sirtuin-1 诱导后会越来越多地产生。
