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* Department of Medicine, Rheumatology Section, Veterans Affairs Health Care System/University of California, San Diego, CA 92161;
Columbia University Department of Surgery, New York, NY 10027;
Joint Diseases Laboratory, Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada;
Bolder BioPATH, University of Colorado, Boulder, CO 80302;
¶ Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
Multiple inflammatory mediators in osteoarthritis (OA) cartilage, including S100/calgranulin ligands of receptor for advanced glycation end products (RAGE), promote chondrocyte hypertrophy, a differentiation state associated with matrix catabolism. In this study, we observed that RAGE knockout was not chondroprotective in instability-induced knee OA in 8-wk-old mice. Hence, we tested the hypothesis that expression of the alternative S100/calgranulin and patterning receptor CD36, identified here as a marker of growth plate chondrocyte hypertrophy, mediates chondrocyte inflammatory and differentiation responses that promote OA. In rat knee joint destabilization-induced OA, RAGE expression was initially sparse throughout cartilage but increased diffusely by 4 wk after surgery. In contrast, CD36 expression focally increased at sites of cartilage injury and colocalized with developing chondrocyte hypertrophy and aggrecan cleavage NITEGE neoepitope formation. However, CD36 transfection in normal human knee-immortalized chondrocytes (CH-8 cells) was associated with decreased capacity of S100A11 and TNF-
to induce chondrocyte hypertrophy and ADAMTS-4 and matrix metalloproteinase 13 expression. S100A11 lost the capacity to inhibit proteoglycans synthesis and gained the capacity to induce proteoglycan synthesis in CD36-transfected CH-8 cells. Moreover, S100A11 required the p38 MAPK pathway kinase MKK3 to induce NITEGE development in mouse articular cartilage explants. However, CH-8 cells transfected with CD36 demonstrated decreased S100A11-induced MKK3 and p38 phosphorylation. Therefore, RAGE and CD36 patterning receptor expression were linked with opposing effects on inflammatory, procatabolic responses to S100A11 and TNF- in chondrocytes.
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 Funded by the Veterans Affairs Research Service, National Institutes of Health (HL077360, AR54135, PAG07998), a Canada Research Chair Award, and awards from the Canadian Institute for Health Research and the Canadian Arthritis Network (to F.B.).
2 Address correspondence and reprint requests to Dr. Robert Terkeltaub, Veterans Affairs Medical Center, Rheumatology, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail address: rterkeltaub{at}ucsd.edu
3 Abbreviations used in this paper: OA, osteoarthritis; ACL, anterior cruciate ligament; ACLT, ACL transection; AGE, advanced glycation end product; GAG, glycosaminoglycan; GW1929, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-L-tyrosine hydrate; HMGB1, high mobility group box protein 1; MKK3, mitogen-activated protein kinase kinase 3; PG, proteoglycan; RAGE, receptor for advanced glycation end product; TIMP3, tissue inhibitor of metalloproteinase 3; IGF-I, insulin-like growth factor I; MMP-13, matrix metalloproteinase 13; PPAR
, peroxisome proliferator-activated receptor .
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