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Inflammation-Induced Chondrocyte Hypertrophy Is Driven by Receptor for Advanced Glycation End Products This information is current as Denise L. Cecil, Kristen Johnson, John Rediske, Martin of September 28, 2021. Lotz, Ann Marie Schmidt and Robert Terkeltaub J Immunol 2005; 175:8296-8302; ; doi: 10.4049/jimmunol.175.12.8296 http://www.jimmunol.org/content/175/12/8296 Downloaded from References This article cites 43 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/175/12/8296.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Inflammation-Induced Chondrocyte Hypertrophy Is Driven by Receptor for Advanced Glycation End Products1 Denise L. Cecil,* Kristen Johnson,* John Rediske,‡ Martin Lotz,§ Ann Marie Schmidt,† and Robert Terkeltaub2* The multiligand receptor for advanced glycation end products (RAGE) mediates certain chronic vascular and neurologic degen- erative diseases accompanied by low-grade inflammation. RAGE ligands include S100/calgranulins, a class of low-molecular-mass, calcium-binding polypeptides, several of which are chondrocyte expressed. Here, we tested the hypothesis that S100A11 and RAGE signaling modulate osteoarthritis (OA) pathogenesis by regulating a shift in chondrocyte differentiation to hypertrophy. We analyzed human cartilages and cultured human articular chondrocytes, and used recombinant human S100A11, soluble RAGE, and previously characterized RAGE-specific blocking Abs. Normal human knee cartilages demonstrated constitutive RAGE and Downloaded from S100A11 expression, and RAGE and S100A11 expression were up-regulated in OA cartilages studied by immunohistochemistry. CXCL8 and TNF-␣ induced S100A11 expression and release in cultured chondrocytes. Moreover, S100A11 induced cell size increase and expression of type X collagen consistent with chondrocyte hypertrophy in vitro. CXCL8-induced, IL-8-induced, and TNF-␣-induced but not retinoic acid-induced chondrocyte hypertrophy were suppressed by treatment with soluble RAGE or RAGE-specific blocking Abs. Last, via transfection of dominant-negative RAGE and dominant-negative MAPK kinase 3, we demonstrated that S100A11-induced chondrocyte type X collagen expression was dependent on RAGE-mediated p38 MAPK http://www.jimmunol.org/ pathway activation. We conclude that up-regulated chondrocyte expression of the RAGE ligand S100A11 in OA cartilage, and RAGE signaling through the p38 MAPK pathway, promote inflammation-associated chondrocyte hypertrophy. RAGE signaling thereby has the potential to contribute to the progression of OA. The Journal of Immunology, 2005, 175: 8296–8302. ow-grade chronic inflammation, mediated partly by the proteinase 13 (MMP-13), and promotion of pathologic calcifica- effects on chondrocytes of cartilage-expressed and syno- tion (8–10). OA cartilages typically develop foci of maturation of L vium-expressed cytokines including IL-1␤, TNF-␣, (IL- cells to hypertrophic differentiation (10). 8)/CXCL8, and (growth-related oncogene ␣)/CXCL1 appear to A growing body of evidence has implicated the receptor for contribute to the progression of osteoarthritis (OA)3 (1–8). Re- advanced glycation end products (RAGE) in certain chronic arte- by guest on September 28, 2021 cently, we linked the induction of altered chondrocyte differenti- rial, renal, and neurologic degenerative conditions associated with ation to chemokine-induced inflammation, by demonstrating that low-grade tissue inflammation (11–14). RAGE is a broadly ex- CXCL8 and CXCL1, both of which are up-regulated in OA car- pressed 45-kDa transmembrane protein bearing a 43-aa cytosolic tilage (6), stimulated chondrocyte hypertrophic differentiation in tail, and three extracellular domains (i.e., the ligand-binding V vitro (8). Chondrocyte hypertrophy can contribute to the progres- (VЈ) domain, and two C domains) that confer RAGE membership sion of OA via effects including dysregulation of matrix repair in the Ig superfamily (11–14). RAGE is a cognate receptor for four through reduced expression of collagen II and aggrecan, increased distinct classes of ligands (11–14), including S100/calgranulins, a expression of type collagen X, up-regulation of matrix metallo- family of Ͼ20 low-molecular-mass (ϳ10–14 kDa), acidic proteins that form homodimers, heterodimers, and larger multimers, and bind calcium via two internal EF-hand motifs in each monomer *Veterans Affairs Medical Center, Department of Medicine, University of California, (14–16). Certain individual S100/calgranulins (S100A1, S100A2, San Diego, CA 92161; †Department of Surgery, College of Physicians and Surgeons, S100A4, S100B) have been reported to be expressed by chondro- Columbia University, New York, NY 10032; ‡Novartis Institutes for Biomedical Research, Cambridge, MA 02139; and §The Scripps Research Institute, La Jolla, CA cytes (17–19), and intense S100 immunoreactivity is a marker of 92037 chondrogenic differentiation (20). In addition, concentrations of Received for publication May 12, 2005. Accepted for publication September certain calgranulins in diseased joint fluids reach nanomolar con- 23, 2005. centrations (21, 22). The costs of publication of this article were defrayed in part by the payment of page Recently, RAGE expression was demonstrated in human artic- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ular cartilage and observed to be more robust in aging and OA 1 This work was supported by a Merit Review grant from Department of Veterans cartilages (18). Furthermore, IL-1 and fibronectin fragments in- Affairs (to R.T.) and by support from the National Institutes of Health (including duced chondrocyte RAGE expression and micromolar S100B in- Grants P01AGO7996, HL077360-01, and AR049366-01A2). duced MMP-13 in chondrocytes mediated by RAGE in vitro (18). 2 Address correspondence and reprint requests to Dr. Robert Terkeltaub, Veterans In this study, we examined the potential role in articular chondro- Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail address: [email protected] cyte hypertrophy of RAGE, with particular focus on RAGE inter- 3 Abbreviations used in this paper: OA, osteoarthritis; MMP, matrix metalloprotein- action with S100A11 (S100C, calgizzarin) (15, 16). Our results ase; RAGE, receptor for advanced glycation end products; ATRA, all-trans retinoic implicate up-regulated S100A11 expression, and RAGE-depen- acid; sRAGE, soluble RAGE; DN, dominant negative; MKK, MAPK kinase; AGE, advanced glycation end products; HMGB-1, high-mobility group box-1; TG2, trans- dent and p38 MAPK-dependent signaling, in inflammatory regu- glutaminase 2. lation of chondrocyte hypertrophic differentiation in OA cartilage. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 8297 Materials and Methods and DN-RAGE were further verified by SDS-PAGE/Western blotting anal- Reagents ysis (26), using the aforementioned murine monoclonal anti-RAGE Ab. Unless otherwise indicated, Western blotting in this study analyzed ali- All-trans retinoic acid (ATRA), and human recombinant CXCL8 and quots of 30-␮g protein obtained from whole-cell lysates, or precipitated TNF-␣ were from R&D Systems, and rabbit polyclonal Abs to type X from conditioned medium using 15% TCA, followed by separation via collagen were from Calbiochem. mAb to RAGE was from Chemicon In- 10% SDS-PAGE. The Western blots used HRP-conjugated secondary Abs, ternational. Soluble human RAGE (sRAGE) and rabbit polyclonal RAGE- as described (26). Immunoreactive products were detected using ECL. Pri- specific functional blocking Abs were as previously characterized (23). mary and secondary Ab dilutions were 1/2000. Abs to type X collagen Human RAGE and dominant-negative (DN) RAGE cDNA in the vector were from Calbiochem, to p38 and phosphorylated p38 were from Cell pCDNA4-V5His (Invitrogen Life Technologies) were as previously de- Signaling, and to ␣-tubulin were from Sigma. HRP-conjugated goat anti- scribed (23, 24). DN-MAPK kinase 3 (MKK3) (25) was generously pro- rabbit IgG and anti-mouse IgG were obtained from Santa Cruz vided by Dr. J. Han (The Scripps Research Institute, La Jolla, CA). Unless Biotechnology. otherwise indicated, all other reagents were obtained from Sigma-Aldrich. Flow cytometric analyses Immunohistochemistry for RAGE and S100A11 Human articular chondrocytes (1 ϫ 106) were permeabilized using the BD Mouse polyclonal Abs recognizing the human S100A11-specific peptide Cytofix/Cytoperm kit (BD Pharmingen). Where indicated, the cells were CHDSFLKAVPSQKRT, which is expressed
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