Yang Jeong-In, Chun Jang-Soo
National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
Arthritis Res Ther. 2021 Apr 14;23(1):114. doi: 10.1186/s13075-021-02485-z.
Ribonucleases (RNases) play central roles in the post-transcriptional regulation of mRNA stability. Our preliminary results revealed that the endonuclease Regnase-1 is specifically upregulated in osteoarthritic chondrocytes. We herein explored the possible functions and regulatory mechanisms of Regnase-1 in a mouse model of osteoarthritis (OA).
The expression and target genes of Regnase-1 were identified by microarray analysis in primary-culture mouse articular chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). The function of Regnase-1 in DMM-induced post-traumatic OA mice was examined by adenovirus-mediated overexpression or knockdown in knee joint tissues, and also by using Regnase-1 heterozygous knockout mice (Zc3h12a).
Among the RNases, Regnase-1 was exclusively upregulated in chondrocytes stimulated with OA-associated catabolic factors. Adenovirus-mediated overexpression or knockdown of Regnase-1 alone in joint tissues did not cause OA-like changes. However, overexpression of Regnase-1 in joint tissues significantly ameliorated DMM-induced post-traumatic OA cartilage destruction, whereas knockdown or genetic ablation of Regnase-1 exacerbated DMM-induced cartilage destruction. Mechanistic studies suggested that Regnase-1 suppresses cartilage destruction by modulating the expression of matrix-degrading enzymes in chondrocytes.
Our results collectively suggest that upregulated Regnase-1 in OA chondrocytes may function as a chondro-protective effector molecule during OA pathogenesis by forming a negative feedback loop of catabolic signals, such as matrix-degrading enzyme expression, in OA chondrocytes.
核糖核酸酶（RNases）在mRNA稳定性的转录后调控中发挥核心作用。我们的初步结果显示，核酸内切酶Regnase-1在骨关节炎软骨细胞中特异性上调。我们在此探讨了Regnase-1在骨关节炎（OA）小鼠模型中的可能功能和调控机制。
通过微阵列分析在原代培养的小鼠关节软骨细胞中鉴定Regnase-1的表达和靶基因。通过内侧半月板不稳定（DMM）诱导小鼠实验性OA。通过腺病毒介导的过表达或在膝关节组织中的敲低，以及使用Regnase-1杂合敲除小鼠（Zc3h12a），研究Regnase-1在DMM诱导的创伤后OA小鼠中的功能。
在核糖核酸酶中，Regnase-1仅在受到OA相关分解代谢因子刺激的软骨细胞中上调。单独在关节组织中腺病毒介导的Regnase-1过表达或敲低不会引起OA样变化。然而，Regnase-1在关节组织中的过表达显著改善了DMM诱导的创伤后OA软骨破坏，而Regnase-1的敲低或基因敲除加剧了DMM诱导的软骨破坏。机制研究表明，Regnase-1通过调节软骨细胞中基质降解酶的表达来抑制软骨破坏。
我们的结果共同表明，OA软骨细胞中上调的Regnase-1可能通过在OA软骨细胞中形成分解代谢信号（如基质降解酶表达）的负反馈环，在OA发病机制中作为软骨保护效应分子发挥作用。
