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J. Biol. Chem., Vol. 282, Issue 15, 11110-11121, April 13, 2007

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Basic Fibroblast Growth Factor Stimulates Matrix Metalloproteinase-13 via the Molecular Cross-talk between the Mitogen-activated Protein Kinases and Protein Kinase C Pathways in Human Adult Articular Chondrocytes^*

Hee-Jeong Im^¶1, Prasuna Muddasani, Viswanathan Natarajan^||, Thomas M. Schmid, Joel A. Block, Francesca Davis, Andre J. van Wijnen^**, and Richard F. Loeser

From the Departments of Biochemistry, Internal Medicine, Section of Rheumatology, and ^¶Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois 60612, the ^||Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois 60637, the ^**Department of Cell Biology, School of Medicine, University of Massachusetts, North Worcester, Massachusetts 01655, and the Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Excessive release of basic fibroblast growth factor (bFGF) during loading and/or injury of the cartilage matrix may contribute to the onset or progression of osteoarthritis. This pathological role may be related to the ability of bFGF to decrease proteoglycan synthesis and to antagonize the activity of anabolic growth factors in cartilage such as insulin-like growth factor-1 and bone morphogenetic protein 7 (BMP7 or OP-1). Matrix metalloproteinase-13 (MMP-13), a catabolic cartilage-degrading enzyme, is dramatically up-regulated by inflammatory cytokines or by fibronectin fragments in articular chondrocytes. In this study, we investigated MMP-13 production by bFGF using human articular chondrocytes. Endogenous concentration of bFGF in synovial fluids collected from arthritis patients and asymptomatic subjects showed a good linear correlation with the endogenous levels of MMP-13. bFGF stimulation of MMP-13 was mediated at the transcriptional level and, at least in part, by stimulation of interleukin-1 production. Also, our findings suggest that bFGF stimulation of MMP-13 required the activation of multiple MAPKs (ERK, p38, and JNK) by bFGF, and more importantly, bFGF activation of protein kinase C (PKC) played a key role in the MMP-13 stimulation. Indeed, PKC is the only isoform associated with MMP-13 stimulation among the PKC isoforms tested. PKC controls the bFGF response by regulating multiple MAPK pathways. Our results suggest that PKC activation is a principal rate-limiting event in the bFGF-dependent stimulation of MMP-13 in human adult articular chondrocytes. We propose that deregulation of cross-talk between MAPK and PKC signaling may contribute to the etiology of osteoarthritis in human patients.

Received for publication, September 22, 2006 , and in revised form, February 6, 2007.

^* This work was supported by the Falk Foundation, a UCR grant from the Rush University Medical Center, The Arthritis National Research Foundation, The Arthritis Foundation (Chicago Chapter grant), National Institutes of Health Grant AR053220 (to H. J. I.), and National Institutes of Health Grant AR49003 (to R. F. L.). 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 To whom correspondence should be addressed: Dept. of Biochemistry, Rush University Medical Center, Cohn Research Bldg. 516, 1735 W. Harrison, Chicago, IL 60612. Tel.: 312-942-3091; Fax: 312-942-3053; E-mail: Hee-Jeong_Sampen{at}rush.edu.

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				P. Muddasani, J. C. Norman, M. Ellman, A. J. van Wijnen, and H.-J. Im Basic Fibroblast Growth Factor Activates the MAPK and NF{kappa}B Pathways That Converge on Elk-1 to Control Production of Matrix Metalloproteinase-13 by Human Adult Articular Chondrocytes J. Biol. Chem., October 26, 2007; 282(43): 31409 - 31421. [Abstract] [Full Text] [PDF]