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Stromal Cell-Derived Factor-1 Induces Matrix Metalloprotease-13 Expression in Human Chondrocytes

Department of Orthopaedics, Taichung Veterans General Hospital, Taichung, Taiwan (Y.-C.C., T.-S.L.); Departments of Orthopaedics (R.-S.Y.) and Pharmacology (W.-M.F.), College of Medicine, National Taiwan University, Taipei, Taiwan; Tung's Taichung MetroHarbor Hospital, Taichung, Taiwan (K.-H.H.); Department of Orthopaedics, China Medical University Hospital, Taichung, Taiwan (Y.-C.F.); and Departments of Pharmacology (Y.-C.C., C.-H.T.) and Biological Science and Technology (T.-D.W.), School of Medicine (H.-C.W.), China Medical University, Taichung, Taiwan

The production of chemokine stromal cell-derived factor (SDF)-1 is significantly higher in synovial fluid of patients with osteoarthritis and rheumatoid arthritis. Matrix metalloproteinase (MMP)-13 may contribute to the breakdown of articular cartilage during arthritis. Here, we found that SDF-1 increased the secretion of MMP-13 in cultured human chondrocytes, as shown by reverse transcriptase-polymerase chain reaction, Western blot, and zymographic analysis. SDF-1 also increased the surface expression of CXCR4 receptor in human chondrocytes. CXCR4-neutralizing antibody, CXCR4-specific inhibitor [1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100)], or small interfering RNA against CXCR4 inhibited the SDF-1-induced increase of MMP-13 expression. The transcriptional regulation of MMP-13 by SDF-1 was mediated by phosphorylation of extracellular signal-regulated kinases (ERK) and activation of the activator protein (AP)-1 components of c-Fos and c-Jun. The binding of c-Fos and c-Jun to the activator protein (AP-1) element on the MMP-13 promoter and the increase in luciferase activity was enhanced by SDF-1. Cotransfection with dominant-negative mutant of ERK2 or c-Fos and c-Jun antisense oligonucleotide inhibited the potentiating action of SDF-1 on MMP-13 promoter activity. Taken together, our results provide evidence that SDF-1 acts through CXCR4 to activate ERK and the downstream transcription factors (c-Fos and c-Jun), resulting in the activation of AP-1 on the MMP-13 promoter and contributing cartilage destruction during arthritis.

Address correspondence to: Dr. Tang Chih-Hsin, Department of Pharmacology, College of Medicine, China Medical University, 91 Hsueh-Shih Rd., Taichung, Taiwan. E-mail: chtang{at}mail.cmu.edu.tw