RRC ID 63769
Author Hu G, Zhang N, Li J, Wang J, Wu W, Li J, Tong W, Zhao X, Dai L, Zhang X.
Title Tumor Necrosis Factor Receptor Associated Factor 3 Modulates Cartilage Degradation through Suppression of Interleukin 17 Signaling.
Journal Am J Pathol
Abstract Interleukin 17A (IL-17A) is critical in the pathogenesis of autoimmune diseases through driving inflammatory cascades. However, the role of IL-17 in osteoarthritis (OA) is not well understood. Tumor necrosis factor-receptor-associated factor 3 (TRAF3) is a receptor proximal negative regulator of IL-17 signaling. It remains unclear whether TRAF3 exerts regulatory effects on cartilage degradation and contributes to the pathogenesis of OA. In this study, we found that TRAF3 notably suppressed IL-17-induced NF-κB and mitogen-activated protein kinase activation and, subsequently, the production of matrix-degrading enzymes. TRAF3 depletion enhanced IL-17 signaling, along with increased matrix-degrading enzyme production. In vivo, cartilage destruction caused by surgery-induced OA was alleviated markedly both in 1l17a-deficient mice and in TRAF3 transgenic mice. In contrast, silencing TRAF3 through adenoviruses worsened cartilage degradation in experimental OA. Moreover, the destructive effect of IL-17 on cartilage was abolished in TRAF3 transgenic mice in an IL-17 intra-articular injection animal model. Similarly, genetic deletion of IL-17 blocked TRAF3 knockdown-mediated promotion of cartilage destruction, suggesting that the protective effect of TRAF3 on cartilage is mediated by its suppression of IL-17 signaling. Collectively, our results suggest that TRAF3 negatively regulates IL-17-mediated cartilage degradation and pathogenesis of OA, and may serve as a potential new therapy target for OA.
Volume 190(8)
Pages 1701-1712
Published 2020-8-1
DOI 10.1016/j.ajpath.2020.04.016
PII S0002-9440(20)30239-X
PMID 32416098
MeSH Animals Arthritis, Experimental / genetics Arthritis, Experimental / metabolism* Arthritis, Experimental / pathology Cartilage, Articular / metabolism* Cartilage, Articular / pathology Chondrocytes / metabolism Chondrocytes / pathology Interleukin-17 / metabolism* Mice Mice, Transgenic NF-kappa B / metabolism Osteoarthritis / genetics Osteoarthritis / metabolism* Osteoarthritis / pathology Signal Transduction / physiology* TNF Receptor-Associated Factor 3 / genetics TNF Receptor-Associated Factor 3 / metabolism*
IF 3.491
Human and Animal Cells ATDC5(RCB0565)