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Adaptor Proteins and Ras Synergistically Regulate IL-1-Induced ADAMTS-4 Expression in Human Chondrocytes ¹

Rasheed Ahmad^*, Judith Sylvester^*, Mushtaq Ahmad and Muhammad Zafarullah^2,*

^* Department of Medicine, University of Montreal and Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Notre-Dame Hospital, Montreal, Quebec, Canada; and Cardiovascular Research Institute (CVRI), Morehouse School of Medicine, Atlanta, GA 30310

Aggrecanases (a dystrophin and metalloproteinase with thrombospondin motif, ADAMTSs) are principal proteases involved in cartilage extracellular matrix aggrecan degradation. The role and relative contribution of MyD88, IRAK1, and TRAF6 adaptor proteins in IL-1β regulation of aggrecanase-1 (ADAMTS-4) is unknown. By small interfering RNAs-mediated knockdown, we show that IL-1β-induced up-regulation of ADAMTS-4 in chondrocytes requires MyD88, IRAK1, and TRAF6 adaptor proteins. However, partial inhibition of ADAMTS-4 induction by their knockdown suggested the involvement of additional signaling proteins. Because IL-1β is also known to induce reactive oxygen species (ROS) through Ras-mediated activation of NADPH oxidase, we investigated the implication of Ras in ADAMTS-4 regulation. Ras knockdown, or inhibition of ROS by antioxidants along with the ablation of MyD88, IRAK1, or TRAF6 more potently down-regulated IL-1β-induced ADAMTS-4. In addition, IL-1β-induced phosphorylation of downstream effectors, IB kinase β, IB, and activation of transcription factor NF-B was significantly reduced in the MyD88-, IRAK1-, TRAF6-, or Ras-deficient cells. The combined knockdown of Ras and individual adaptor proteins strongly blocked the activation of IKKβ, IB, and NF-B. These findings suggest that Ras, ROS along with MyD88, IRAK1, or TRAF6 synergistically mediate ADAMTS-4 regulation by IL1-β. Thus, complete ablation of ADAMTS-4 induction could be achieved by combined inhibition of Ras and individual adaptor proteins, which may be of therapeutic value in arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant (to M.Z.) and a fellowship (to R.A.) from the Canadian Institutes of Health Research and start-up funds (to M.A.) from Morehouse School of Medicine.

² Address correspondence and reprint requests to Dr. M. Zafarullah, K-5255 Mailloux, Hôpital Notre-Dame du Centre Hospitalier de l’Université de Montréal, 1560 Sherbrooke est, Montréal, Québec, Canada H2L 4M1. E-mail address: Muhammad.Zafarullah{at}umontreal.ca

³ Abbreviations used in this paper: ECM, extracellular matrix; RA, rheumatoid arthritis; OA, osteoarthritis; ADAMTS, A dystrophin and metalloproteinase with thrombospondin motif; IRAK1, IL-1R-associated kinase; TRAF6, TNF receptor-associated factor 6; siRNA, small interfering RNA; ROS, reactive oxygen species; IKK, IB kinase; MMP-13, matrix metalloproteinase-13; NDGA, nordihydroguaiaretic acid.