Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Int Immunopharmacol. 2023 Oct;123:110651. doi: 10.1016/j.intimp.2023.110651. Epub 2023 Jul 26.
Osteoarthritis (OA) is an age-related chronic degenerative disease with complex pathophysiological mechanisms. Accumulating evidence indicates that nod-like receptor pyrin domain 3 (NLRP3) inflammasome-mediated pyroptosis of chondrocytes plays a crucial role in the OA progression. Transient Receptor Potential Vanilloid 4 (TRPV4), described as a calcium-permeable cation channel, isassociated with proinflammatory factors and pyroptosis. In this study, we studied the potential functions of TRPV4 in chondrocyte pyroptosis and cartilage degradation. We found that lipopolysaccharides(LPS)-induced mitochondrial reactive oxygen species (mtROS) accumulation aggravated chondrocyte pyroptosis and cartilage degeneration. TRPV4 induces dynamin-related protein 1 (Drp1) mitochondrial translocation through the Ca-calmodulin-dependent protein kinase II (CaMKII) signaling pathway, which subsequently caused the mitochondrial dysfunction (e.g., mPTP over opening; Δψm depolarization; ATP production decreased; mtROS accumulation), pyroptosis and extracellular matrix (ECM) degradation through hexokinase 2 (HK2) dissociation from mitochondrial membrane. Moreover, TRPV4 inhibition reversed Drp1-involved chondrocyte pyroptosis and cartilage degeneration in the anterior cruciate ligament transection (ACLT) mouse model. Our findings revealed the internal mechanisms underlying TRPV4 regulation in chondrocytes and its intrinsic therapeutic efficacy for OA.
骨关节炎（OA）是一种与年龄相关的慢性退行性疾病，具有复杂的病理生理机制。越来越多的证据表明，核仁素受体吡咯啉域 3（NLRP3）炎性体介导体软骨细胞的细胞焦亡在 OA 进展中起着关键作用。瞬时受体电位香草醛 4（TRPV4）被描述为一种钙通透性阳离子通道，与促炎因子和细胞焦亡有关。在本研究中，我们研究了 TRPV4 在软骨细胞细胞焦亡和软骨降解中的潜在功能。我们发现脂多糖（LPS）诱导的线粒体活性氧（mtROS）积累加重了软骨细胞细胞焦亡和软骨退化。TRPV4 通过 Ca-钙调蛋白依赖性蛋白激酶 II（CaMKII）信号通路诱导动力相关蛋白 1（Drp1）线粒体易位，随后导致线粒体功能障碍（例如，mPTP 过度开放；Δψm 去极化；ATP 产生减少；mtROS 积累）、细胞焦亡和细胞外基质（ECM）降解，通过己糖激酶 2（HK2）从线粒体膜解离。此外，TRPV4 抑制逆转了前交叉韧带横断（ACLT）小鼠模型中 Drp1 介导的软骨细胞细胞焦亡和软骨退化。我们的研究结果揭示了 TRPV4 在软骨细胞中的调节内在机制及其对 OA 的内在治疗效果。
