A crucial role of arginase-2 in osteoarthritis pathogenesis

Abstract

Purpose: Osteoarthritis (OA) appears to be associated with various metabolic disorders. However, a role of amino acids metabolism in OA pathogenesis has not been clearly elucidated to date. Here, we explored whether alterations in amino acid metabolism in chondrocytes regulates OA pathogenesis. Methods: Expression profiles of genes regulating amino acid metabolism in primary-culture mouse chondrocytes was examined by microarray analysis. Expression pattern of the identified genes were further characterized in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The function of Arg2 was examined by analyzing Arg2-/- mice and those subjected to IA injection of an adenovirus encoding Arg2(Ad-Arg2). Results: Microarray analysis revealed that arginase-2 (Arg2), an arginine metabolizing enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human OA patients and various mouse models. Adenovirus-mediated overexpression of Arg2 in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice (Arg2-/-) abolished all manifestations of DMM-induced OA. Mechanistically, Arg2 appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (MMP3 and MMP13) in chondrocytes via the NF-κB pathway. Conclusions: Our results collectively indicate that Arg2 is a crucial catabolic regulator of OA pathogenesis, supporting the notion that Arg2 could be a therapeutic target for the treatment of OA pathogenesis.