National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, 54538, Republic of Korea.
Nat Commun. 2019 Jan 8;10(1):77. doi: 10.1038/s41467-018-08035-7.
Osteoarthritis (OA) is a whole-joint disease characterized by cartilage destruction and other whole-joint pathological changes. There is currently no effective disease-modifying therapy. Here we investigate the post-transcriptional mRNA regulation of OA-modulating proteins in chondrocytes and show that the ZFP36 family member, ZFP36L1, is specifically upregulated in OA chondrocytes and OA cartilage of humans and mice. Adenovirus-mediated overexpression of ZFP36L1 alone in mouse knee-joint tissue does not modulate OA pathogenesis. However, genetic ablation or silencing of Zfp36l1 significantly abrogates experimental OA in mice. Knockdown of Zfp36l1 increases the mRNA expression of two heat shock protein 70 (HSP70) family members, which act as its direct targets. Furthermore, overexpression of HSPA1A in joint tissues protects mice against experimental OA by inhibiting chondrocyte apoptosis. Our results indicate that the RNA-binding protein, ZFP36L1, regulates HSP70 family members that appear to protect against OA pathogenesis by inhibiting chondrocyte apoptosis.
骨关节炎（OA）是一种以软骨破坏和其他整个关节病变为特征的全关节疾病。目前尚无有效的疾病修饰治疗方法。在这里，我们研究了软骨细胞中 OA 调节蛋白的转录后 mRNA 调节，并表明 ZFP36 家族成员 ZFP36L1 在 OA 软骨细胞和人类及小鼠的 OA 软骨中特异性地上调。单独用腺病毒介导的 ZFP36L1 过表达在小鼠膝关节组织中不会调节 OA 发病机制。然而，Zfp36l1 的基因缺失或沉默可显著阻断小鼠的实验性 OA。Zfp36l1 的敲低增加了两个热休克蛋白 70（HSP70）家族成员的 mRNA 表达，它们是其直接靶点。此外，HSPA1A 在关节组织中的过表达通过抑制软骨细胞凋亡来保护小鼠免受实验性 OA 的侵害。我们的研究结果表明，RNA 结合蛋白 ZFP36L1 调节 HSP70 家族成员，这些成员似乎通过抑制软骨细胞凋亡来保护 OA 发病机制。
