Hyaline cartilage fibrosis is typically considered an end-stage pathology of osteoarthritis (OA), which results in changes to the extracellular matrix. However, the mechanism behind this is largely unclear. Here, we found that the RNA helicase DDX5 was dramatically downregulated during the progression of OA. DDX5 deficiency increased fibrosis phenotype by upregulating COL1 expression and downregulating COL2 expression. In addition, loss of DDX5 aggravated cartilage degradation by inducing the production of cartilage-degrading enzymes. Chondrocyte-specific deletion of Ddx5 led to more severe cartilage lesions in the mouse OA model. Mechanistically, weakened DDX5 resulted in abundance of the Fn1-AS-WT and Plod2-AS-WT transcripts, which promoted expression of fibrosis-related genes (Col1, Acta2) and extracellular matrix degradation genes (Mmp13, Nos2 and so on), respectively. Additionally, loss of DDX5 prevented the unfolding Col2 promoter G-quadruplex, thereby reducing COL2 production. Together, our data suggest that strategies aimed at the upregulation of DDX5 hold significant potential for the treatment of cartilage fibrosis and degradation in OA.

透明软骨纤维化通常被认为是骨关节炎 (OA) 的终末期病理，它会导致细胞外基质的变化。然而，这背后的机制很大程度上尚不清楚。在这里，我们发现 RNA 解旋酶 DDX5 在 OA 进展过程中显着下调。 DDX5 缺陷通过上调 COL1 表达和下调 COL2 表达来增加纤维化表型。此外，DDX5的缺失会诱导软骨降解酶的产生，从而加剧软骨降解。软骨细胞特异性删除Ddx5会导致小鼠 OA 模型中更严重的软骨损伤。从机制上讲，DDX5减弱导致Fn1 -AS-WT和Plod2 -AS-WT转录本丰富，分别促进纤维化相关基因（ Col1 、 Acta2 ）和细胞外基质降解基因（ Mmp13 、 Nos2等）的表达。此外，DDX5 的缺失阻止了Col2启动子 G-四链体的展开，从而减少了 COL2 的产生。总之，我们的数据表明，旨在上调 DDX5 的策略对于治疗 OA 软骨纤维化和退化具有巨大潜力。