PT  - JOURNAL ARTICLE
AU  - Yung-Cheng Chiu
AU  - Rong-Sen Yang
AU  - Kuo-Hsien Hsieh
AU  - Yi-Chin Fong
AU  - Tzong-Der Way
AU  - Tu-Sheng Lee
AU  - Hsi-Chin Wu
AU  - Wen-Mei Fu
AU  - Chih-Hsin Tang
TI  - Stromal Cell-Derived Factor-1 Induces Matrix Metalloprotease-13 Expression in Human Chondrocytes
AID  - 10.1124/mol.107.036541
DP  - 2007 Sep 01
TA  - Molecular Pharmacology
PG  - 695--703
VI  - 72
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/72/3/695.short
4100  - http://molpharm.aspetjournals.org/content/72/3/695.full
SO  - Mol Pharmacol2007 Sep 01; 72
AB  - 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-1α increased the secretion of MMP-13 in cultured human chondrocytes, as shown by reverse transcriptase-polymerase chain reaction, Western blot, and zymographic analysis. SDF-1α 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-1α-induced increase of MMP-13 expression. The transcriptional regulation of MMP-13 by SDF-1α 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-1α. Cotransfection with dominant-negative mutant of ERK2 or c-Fos and c-Jun antisense oligonucleotide inhibited the potentiating action of SDF-1α on MMP-13 promoter activity. Taken together, our results provide evidence that SDF-1α 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. The American Society for Pharmacology and Experimental Therapeutics