Stromal cell-derived factor-1 induces matrix metalloprotease13 expression in human Chondrocytes

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 alpha 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 alpha 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 alpha induced increase of MMP- 13 expression. The transcriptional regulation of MMP- 13 by SDF- 1 alpha 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 alpha. Cotransfection with dominant- negative mutant of ERK2 or c- Fos and c- Jun antisense oligonucleotide inhibited the potentiating action of SDF- 1 alpha on MMP- 13 promoter activity. Taken together, our results provide evidence that SDF- 1 alpha 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.