Stromal cell-derived factor-1 induces matrix metalloprotease-13 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-1alpha increased the secretion of MMP-13 in cultured human chondrocytes, as shown by reverse transcriptase-polymerase chain reaction, Western blot, and zymographic analysis. SDF-1alpha 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-1alpha-induced increase of MMP-13 expression. The transcriptional regulation of MMP-13 by SDF-1alpha 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-1alpha. Cotransfection with dominant-negative mutant of ERK2 or c-Fos and c-Jun antisense oligonucleotide inhibited the potentiating action of SDF-1alpha on MMP-13 promoter activity. Taken together, our results provide evidence that SDF-1alpha 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.
Chiu
Yung-Cheng
YC
Department of Orthopaedics, Taichung Veterans General Hospital, Taichung, Taiwan.
Yang
Rong-Sen
RS
Hsieh
Kuo-Hsien
KH
Fong
Yi-Chin
YC
Way
Tzong-Der
TD
Lee
Tu-Sheng
TS
Wu
Hsi-Chin
HC
Fu
Wen-Mei
WM
Tang
Chih-Hsin
CH
D019380:Anti-HIV Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001596:Benzylamines; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000032:analysis / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019902:Chondrocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism*; D000080027:Cyclams; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D013582:Synovial Fluid / Q000737:chemistry; D013583:Synovial Membrane / Q000166:cytology
D019380:Anti-HIV Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000080027:Cyclams; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D053509:Matrix Metalloproteinase 13; C088327:plerixafor