Stromal cell-derived factor-1 induces matrix metalloprotease-13 expression in human chondrocytes
Journal
Molecular Pharmacology
Journal Volume
72
Journal Issue
3
Pages
695-703
Date Issued
2007
Author(s)
Abstract
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. Copyright ? 2007 The American Society for Pharmacology and Experimental Therapeutics.
SDGs
Other Subjects
1,1' [1,4 phenylenebis(methylene)]bis(1,4,8,11 tetraazacyclotetradecane); 2 (2 amino 3 methoxyphenyl)chromone; 2 morpholino 8 phenylchromone; 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole; anthra[1,9 cd]pyrazol 6(2h) one; chemokine receptor CXCR4; collagenase 3; messenger RNA; protein c fos; protein c jun; small interfering RNA; stromal cell derived factor 1; transcription factor AP 1; article; articular cartilage; bone destruction; cartilage cell; controlled study; drug effect; drug inhibition; enzyme phosphorylation; flow cytometry; human; human cell; immunoprecipitation; osteoarthritis; priority journal; protein expression; reverse transcription polymerase chain reaction; rheumatoid arthritis; synovial fluid; transcription regulation; Western blotting; zymography; Anti-HIV Agents; Arthritis, Rheumatoid; Cells, Cultured; Chemokines, CXC; Chondrocytes; Dose-Response Relationship, Drug; Heterocyclic Compounds; Humans; Matrix Metalloproteinase 13; Osteoarthritis; Receptors, CXCR4; RNA, Messenger; RNA, Small Interfering; Stromal Cells; Synovial Fluid; Synovial Membrane
Type
journal article