Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor.
Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor.
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DOI：
10.1002/art.40552
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Liu CJ
中科院分区：
文献类型：
--
作者：
Wei JL;Fu W;Hettinghouse A;He WJ;Lipson KE;Liu CJ
It has been reported that a disintegrin and metalloproteinase with thrombospondin motifs-12 (ADAMTS-12) is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS-12 was also reported to be required for normal inflammation. This study aims to determine the role of ADAMTS-12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis. The collagen-induced arthritis (CIA) model was established in ADAMTS-12-deficient mice and their control littermates to determine the role of ADAMTS-12 in vivo; microCT scanning was used to demonstrate the destruction of ankle joint; histological analysis illustrated synovitis, pannus formation, as well as bone and cartilage destruction; ELISA was performed to measure serum levels of inflammatory cytokines; Protein-protein interaction assays were performed to detect the interactions of ADAMTS-12 and its various deletion mutants with connective tissue growth factor (CTGF). Deficiency of ADAMTS-12 leads to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS-12 causes enhanced osteoclastogenesis. In vitro and in vivo protein-protein interaction assays demonstrate CTGF, a previously unrecognized substrate of ADAMTS-12, binding and processing by ADAMTS-12. In addition, deletion of ADAMTS-12 enhances, while overexpression of ADMATS-12 reduces, CTGF-mediated inflammation. Furthermore, ADAMTS-12 regulation of inflammation is largely lost in CTGF deficient macrophages. Importantly, blocking CTGF attenuates elevated inflammatory arthritis seen in ADAMTS-12-deficient CIA mouse model. ADAMTS-12 proves to be a critical regulator of inflammatory arthritis through, at least in part, controlling CTGF turnover.
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