Critical role for arginase II in osteoarthritis pathogenesis

Abstract

ObjectiveOsteoarthritis (OA) appears to be associated with various metabolic disorders, but the potential contribution of amino acid metabolism to OA pathogenesis has not been clearly elucidated. Here, we explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis.MethodsExpression profiles of amino acid metabolism-regulating genes in primary-culture passage 0 mouse chondrocytes were examined by microarray analysis, and selected genes were further characterised in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The functional consequences of arginase II (Arg-II) were examined in Arg2−/− mice and those subjected to IA injection of an adenovirus encoding Arg-II (Ad-Arg-II).ResultsThe gene encoding Arg-II, an arginine-metabolising enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human patients with OA and various mouse models. 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 DMM-induced OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (matrix metalloproteinase 3 [MMP3] and MMP13) in chondrocytes via the nuclear factor (NF)-κB pathway.ConclusionsOur results indicate that Arg-II is a crucial regulator of OA pathogenesis in mice. Although chondrocytes of human and mouse do not identically, but similarly, respond to Arg-II, our results suggest that Arg-II could be a therapeutic target of OA pathogenesis.

Arginase 2 Deficiency Promotes Neuroinflammation and Pain Behaviors Following Nerve Injury in Mice

“…In this study, we considered the upregulation of Arg2 in the spinal cord of SNT mice to be more detrimental, but then how could we explain the more severe pain state in mice with a lack of Arg2? A study on osteoarthritis (OA) demonstrated the detrimental role of Arg2 in promoting inflammation when it was overexpressed [13]. In that study, they have demonstrated that Arg2 overexpression in mouse joint tissues causes OA with synovitis and loss of glycosaminoglycans in articular cartilage followed by upregulation of pro-inflammatory products, although, their data show ablation of Arg2 promoted IL-1β caused NO production.…”

“…In fact, several recent studies on various diseases and disorders have reported that upregulation of Arg2 has detrimental effects on the pathogenic process. For example, Arg2 overexpression has been demonstrated to contribute to the destruction of osteoarthritis cartilage and osteoarthritis pathogenesis [13]. In particular, in diseases associated with metabolic disorders, such as diabetes, Arg2 has been shown to play a causal role in the induction of diabetic renal injury [12].…”

“…Arg2 has been demonstrated to contribute to diabetic renal injury in mice with diabetes [12]. A recent study published in 2019 showed the detrimental role of Arg2 overexpression in the pathogenesis of osteoarthritis [13] when it upregulated pro-inflammatory cytokines in osteoarthritis cartilage. However, those data also revealed that the overexpression of Arg2 significantly reduces interleukin (IL)-1β-caused NO production, which appears as a pro-inflammatory marker, and that the knockdown of Arg2 increases IL-1β-induced NO levels [13].…”

“…A recent study published in 2019 showed the detrimental role of Arg2 overexpression in the pathogenesis of osteoarthritis [13] when it upregulated pro-inflammatory cytokines in osteoarthritis cartilage. However, those data also revealed that the overexpression of Arg2 significantly reduces interleukin (IL)-1β-caused NO production, which appears as a pro-inflammatory marker, and that the knockdown of Arg2 increases IL-1β-induced NO levels [13]. Taken together, these studies suggest that Arg1 and Arg2 may play similar or different roles depending on the cells or organs in which they are located [11].…”

<p>Salidroside Alleviates Cartilage Degeneration Through NF-κB Pathway in Osteoarthritis Rats</p>

“…26 Besides, Choi et al believed that the NF-κB pathway may be involved in Arg-II-induced OA cartilage injury by upregulating the levels of MMP3 and MMP13. 27 In this study, we elucidated the deeper molecular mechanism of Sal in OA, which laid the foundation for Sal as a clinical drug of OA.…”