Up-regulated Endonuclease Regnase-1 Suppresses Osteoarthritis by Forming Negative Feedback Loop of Catabolic Signaling in Chondrocytes

Abstract

Background: Ribonucleases (RNases) play central roles in the post-transcriptional regulation of mRNA stability. Our preliminary results revealed that the endonuclease Regnase-1 is specifically up-regulated in osteoarthritic chondrocytes. We herein explored the possible functions and regulatory mechanisms of Regnase-1 in a mouse model of osteoarthritis (OA).Methods: 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+/-). Results: Among the RNases, Regnase-1 was exclusively up-regulated 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 showed that Regnase-1 appears to suppress cartilage destruction by modulating the expression of matrix-degrading enzymes in chondrocytes. Conclusion: Our results collectively suggest that up-regulated Regnase-1 in OA chondrocytes may function as a chondro-protective effector molecule during OA pathogenesis by forming negative feedback loop of catabolic signaling such as expression of matrix-degrading enzymes in OA chondrocytes.