Department of Neurology, Duke University, Durham, NC 27710;
Department of Biomedical Engineering, University of Rochester, Rochester, NY 14620.
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2001611118.
Osteoarthritis (OA) is a painful and debilitating condition of synovial joints without any disease-modifying therapies [A. M. Valdes, T. D. Spector, 7, 23-32 (2011)]. We previously identified mechanosensitive PIEZO channels, PIEZO1 and PIEZO2, both expressed in articular cartilage, to function in chondrocyte mechanotransduction in response to injury [W. Lee , 111, E5114-E5122 (2014); W. Lee, F. Guilak, W. Liedtke, 79, 263-273 (2017)]. We therefore asked whether interleukin-1-mediated inflammatory signaling, as occurs in OA, influences iezo gene expression and channel function, thus indicative of maladaptive reprogramming that can be rationally targeted. Primary porcine chondrocyte culture and human osteoarthritic cartilage tissue were studied. We found that interleukin-1α (IL-1α) up-regulated Piezo1 in porcine chondrocytes. Piezo1 expression was significantly increased in human osteoarthritic cartilage. Increased Piezo1 expression in chondrocytes resulted in a feed-forward pathomechanism whereby increased function of Piezo1 induced excess intracellular Ca at baseline and in response to mechanical deformation. Elevated resting state Ca in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation microtrauma. As intracellular substrates of this OA-related inflammatory pathomechanism, in porcine articular chondrocytes exposed to IL-1α, we discovered that enhanced Piezo1 expression depended on p38 MAP-kinase and transcription factors HNF4 and ATF2/CREBP1. CREBP1 directly bound to the proximal gene promoter. Taken together, these signaling and genetic reprogramming events represent a detrimental Ca-driven feed-forward mechanism that can be rationally targeted to stem the progression of OA.
骨关节炎（OA）是一种痛苦且使人虚弱的滑膜关节疾病，目前尚无任何疾病修饰疗法[AM Valdes，TD Spector，7，23-32（2011）]。我们之前发现，机械敏感的 PIEZO 通道 PIEZO1 和 PIEZO2 均在关节软骨中表达，在软骨细胞的机械转导中发挥作用，以响应损伤[W Lee，111，E5114-E5122（2014）；W Lee，F Guilak，W Liedtke，79，263-273（2017）]。因此，我们询问白细胞介素 1（IL-1）介导的炎症信号是否影响 iezo 基因表达和通道功能，从而表明存在适应性重编程，可以合理靶向。研究了原代猪软骨细胞培养物和人骨关节炎软骨组织。我们发现白细胞介素 1α（IL-1α）上调了猪软骨细胞中的 Piezo1。人骨关节炎软骨中 Piezo1 的表达显著增加。软骨细胞中 Piezo1 表达的增加导致了一种正反馈病理机制，其中 Piezo1 功能的增加导致基础状态和机械变形时细胞内 Ca 过度增加。升高的静息状态 Ca 反过来使 F-肌动蛋白细胞骨架稀疏，并放大机械诱导的变形微创伤。作为这种与 OA 相关的炎症病理机制的细胞内底物，我们在暴露于 IL-1α的猪关节软骨细胞中发现，增强的 Piezo1 表达取决于 p38 MAP 激酶和转录因子 HNF4 和 ATF2/CREBP1。CREBP1 直接与近端基因启动子结合。总的来说，这些信号和遗传重编程事件代表了一种有害的 Ca 驱动的正反馈机制，可以合理靶向以阻止 OA 的进展。
