The role of arginase-Ⅱ and ZC3H12A in osteoarthritis pathogenesis

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease and it leads to enormous social and economic consequences. However, there is currently no effective disease-modifying therapy. This whole- joint disease involves cartilage destruction, synovitis, osteophyte formation, and subchondral bone remodeling. Among these conditions, cartilage destruction is a hallmark of OA caused by the imbalance of catabolic and anabolic homeostasis. Recently, OA appears to be associated with various metabolic disorders, but the potential contribution of amino acid or RNases metabolism to OA pathogenesis has not been elucidated. Herein, I focused on amino acid alteration and the function of RNases, respectively, as regulatory factors in OA pathogenesis. In part Ⅰ, I explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis. A gene encoding arginase-II (Arg-II), an arginine metabolizing enzyme, was up-regulated explicitly in chondrocytes under various pathological conditions and in OA cartilage from human OA patients and various mouse models of OA. Adenovirus-mediated overexpression of Arg-II in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice (Arg2−/−) abolished all manifestations of post-traumatic OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by up-regulating the expression of matrix-degrading enzymes [matrix metalloproteinase 3 (MMP3)and MMP13] in chondrocytes via the nuclear factor (NF)-κB pathway. The results collectively indicate that Arg-II is a crucial catabolic regulator of OA pathogenesis in mice, and that Arg-II could be a therapeutic target of OA pathogenesis. In part Ⅱ, I explored the role of ZC3H12A, an RNA-binding protein, in OA pathogenesis. ZC3H12A is specifically up-regulated in chondrocytes stimulated with OA-associated catabolic signaling. Because the role of ZC3H12A in OA pathogenesis has not been investigated, I explored the molecular targets of ZC3H12A, which may act as an RNase in OA pathogenesis. Adenovirus-mediated overexpression of ZC3H12A in mouse chondrocytes or joint tissues did not affect cartilage homeostasis. However, overexpression of ZC3H12A in joint tissues, enhanced DMM (destabilization of medial meniscus)-induced OA cartilage destruction. In contrast, haplodeficiency of Zc3h12a (Zc3h12a+/-) in mice accelerated DMM-induced cartilage destruction. Consistently, shRNA-mediated ZC3H12A silencing in mouse joint tissue also promoted DMM-induced cartilage destruction. Finally, serum amyloid A3 (SAA3) was identified as a target of ZC3H12A in chondrocytes. However, SAA3 alone did not affect OA pathogenesis. In conclusion, ZC3H12A suppresses experimental OA in mice, and it may be a potential therapeutic target for the treatment of OA.