PMID- 30610061 OWN - NLM STAT- MEDLINE DCOM- 20191202 LR - 20200309 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 78 IP - 3 DP - 2019 Mar TI - Critical role for arginase II in osteoarthritis pathogenesis. PG - 421-428 LID - 10.1136/annrheumdis-2018-214282 [doi] AB - OBJECTIVE: Osteoarthritis (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. METHODS: Expression 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). RESULTS: The 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)-kappaB pathway. CONCLUSIONS: Our 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. CI - (c) Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Choi, Wan-Su AU - Choi WS AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. FAU - Yang, Jeong-In AU - Yang JI AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. FAU - Kim, Wihak AU - Kim W AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. FAU - Kim, Hyo-Eun AU - Kim HE AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. FAU - Kim, Seul-Ki AU - Kim SK AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. FAU - Won, Yoonkyung AU - Won Y AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. FAU - Son, Young-Ok AU - Son YO AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. FAU - Chun, Churl-Hong AU - Chun CH AD - Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Republic of Korea. FAU - Chun, Jang-Soo AU - Chun JS AD - National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea jschun@gist.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190104 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - EC 3.4.24.- (Matrix Metalloproteinase 13) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.5.3.1 (Arg2 protein, mouse) RN - EC 3.5.3.1 (Arginase) SB - IM MH - Animals MH - Arginase/*physiology MH - Arthritis, Experimental/chemically induced/*enzymology MH - Cartilage, Articular/*enzymology MH - Chondrocytes/*enzymology MH - Disease Models, Animal MH - Humans MH - Matrix Metalloproteinase 13/metabolism MH - Matrix Metalloproteinase 3/metabolism MH - Mice MH - Osteoarthritis/chemically induced/*enzymology MH - Up-Regulation PMC - PMC6390026 OTO - NOTNLM OT - arginase II OT - cartilage OT - chondrocytes OT - matrix metalloproteinases OT - osteoarthritis COIS- Competing interests: None declared. EDAT- 2019/01/06 06:00 MHDA- 2019/12/04 06:00 PMCR- 2019/02/26 CRDT- 2019/01/06 06:00 PHST- 2018/08/14 00:00 [received] PHST- 2018/12/04 00:00 [revised] PHST- 2018/12/05 00:00 [accepted] PHST- 2019/01/06 06:00 [pubmed] PHST- 2019/12/04 06:00 [medline] PHST- 2019/01/06 06:00 [entrez] PHST- 2019/02/26 00:00 [pmc-release] AID - annrheumdis-2018-214282 [pii] AID - 10.1136/annrheumdis-2018-214282 [doi] PST - ppublish SO - Ann Rheum Dis. 2019 Mar;78(3):421-428. doi: 10.1136/annrheumdis-2018-214282. Epub 2019 Jan 4.