Received for publication March 29, 2007.
Revised June 3, 2007.
Accepted for publication June 4, 2007.

Stromal cell-derived factor-1 induces matrix metalloprotease-13 expression in human chondrocytes

Abstract

The chemokine stromal cell-derived factor-1 (SDF-1) is significantly higher in synovial fluid of patients with osteoarthritis and rheumatoid arthritis. Matrix metalloproteinases (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 (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 exracelluar signal-regulated kinases (ERK) and activation of the AP-1 components of c-Fos and c-Jun. The binding of c-Fos and c-Jun to the AP-1 element on the MMP-13 promoter and the increase of 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 contribute cartilage destruction during arthritis.

Key words: MAP Kinase, Jun Kinase, AP-1