CITED2 mediates the cross‐talk between mechanical loading and IL‐4 to promote chondroprotection. Issue 1 (19th March 2019)

• Record Type: Journal Article
• Authors: He, Zhiyong; Leong, Daniel J.; Xu, Lin; Hardin, John A.; Majeska, Robert J.; Schaffler, Mitchell B.; Thi, Mia M.; Yang, Liu; Goldring, Mary B.; Cobelli, Neil J.; Sun, Hui B.
• Editors: Sun, Hui B.
• Is Part Of: Annals of the New York Academy of Sciences. Volume 1442:Issue 1(2019)
• Page Start: 128
• Page End: 137
• Publication Date: 2019-03-19
• Subjects: CITED2 -- MMP13 -- IL‐4 -- inflammation -- cartilage degradation -- osteoarthritis; Medical sciences -- Periodicals; Medicine -- Periodicals; Science -- Periodicals; 610
• DOI: 10.1111/nyas.14021
• Languages: English
• ISSNs: 0077-8923

Abstract

Abstract: Osteoarthritis (OA) pathogenesis is mediated largely through the actions of proteolytic enzymes such as matrix metalloproteinase (MMP) 13. The transcriptional regulator CITED2, which suppresses the expression of MMP13 in chondrocytes, is induced by interleukin (IL)‐4 in T cells and macrophages, and by moderate mechanical loading in chondrocytes. We tested the hypothesis that CITED2 mediates cross‐talk between IL‐4 signaling and mechanical loading‐induced pathways that result in chondroprotection, at least in part, by downregulating MMP13. IL‐4 induced CITED2 gene expression in human chondrocytes in a dose‐ and time‐dependent manner through JAK/STAT signaling. Mechanical loading combined with IL‐4 resulted in additive effects on inducing CITED2 expression and downregulating of MMP13 in human chondrocytes in vitro . In vivo, IL‐4 gene knockout (KO) mice exhibited reduced basal levels of CITED2 expression in chondrocytes. While moderate treadmill running induced CITED2 expression and reduced MMP13 expression in wild‐type mice, these effects were blunted (for CITED2) or abolished (for MMP13) in chondrocytes of IL‐4 gene KO mice. Moreover, intra‐articular injections of mouse recombinant IL‐4 combined with regular cage activity mitigated post‐traumatic OA to a greater degree compared to immobilized mice treated with IL‐4 alone. These data suggest that using moderate loading to enhance IL‐4 may be a potential therapeutic strategy for chondroprotection in OA. Abstract : Osteoarthritis pathogenesis is mediated largely through the actions of proteolytic enzymes such as MMP13. The transcriptional regulator CITED2, which suppresses expression of MMP13 in chondrocytes, is induced by interleukin (IL)‐4 in T cells and macrophages, and by moderate mechanical loading in chondrocytes. This paper tests the hypothesis that CITED2 mediates cross‐talk between IL‐4 signaling and mechanical loading‐induced pathways that result in chondroprotection, at least in part, by downregulating MMP13.