MMP-3 expression and release by rheumatoid arthritis fibroblast-like synoviocytes induced with a bacterial ligand of integrin alpha5beta1.
Fibroblast-like synoviocytes (FLSs) play a major role in the pathogenesis of rheumatoid arthritis (RA) by secreting effector molecules that promote inflammation and joint destruction. How these cells become and remain activated is still elusive. Both genetic and environmental factors probably play a role in transforming FLSs into inflammatory matrix-degrading cells. As bacterial products have been detected in the joint and shown to trigger joint inflammation, this study was undertaken to investigate whether a bacterial ligand of integrin alpha5beta1, protein I/II, could contribute to the aggressive behavior of RA FLSs. Protein I/II is a pathogen-associated molecular pattern (PAMP) isolated from oral streptococci that have been identified in the joints of RA patients. The response of RA and osteoarthritis FLSs to protein I/II was analyzed using human cancer cDNA expression arrays. RT-PCR and pro-MMP-3 (pro-matrix metalloproteinase) assays were then performed to confirm the up-regulation of gene expression. Protein I/II modulated about 6% of all profiled genes. Three of these, those encoding IL-6, leukemia inhibitory factor, and MMP-3, showed a high expression level in all RA FLSs tested, whereas the expression of genes encoding other members of the cytokine or MMP-family was not affected. Furthermore, the up-regulation of MMP-3 gene expression was followed by an increase of pro-MMP-3 release. The expression of interferon regulatory factor 1 and fibroblast growth factor-5 was also up-regulated, although the expression levels were lower. Only one gene, that for insulin-like growth factor binding protein-4, was down-regulated in all RA FLSs. In contrast, in osteoarthritis FLSs only one gene, that for IL-6, was modulated. These results suggest that a bacterial ligand of integrin alpha5beta1 may contribute to the aggressive behavior of RA FLSs by inducing the release of pro-inflammatory cytokines and a cartilage-degrading enzyme, such as IL-6 and MMP-3, respectively.
Zeisel
Mirjam B
MB
Inserm 392, Infection et Inflammation, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch, France. zeisel@pharma.u-strasbg.fr
Druet
Vanessa A
VA
Wachsmann
Dominique
D
Sibilia
Jean
J
D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D001426:Bacterial Proteins / Q000235:genetics / Q000494:pharmacology*; D002473:Cell Wall / Q000737:chemistry; D004790:Enzyme Induction / Q000187:drug effects; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000235:genetics; D051521:Fibroblast Growth Factor 5 / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D039081:Integrin alpha5beta1 / Q000187:drug effects* / Q000502:physiology; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D053605:Leukemia Inhibitory Factor; D008024:Ligands; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis* / Q000378:metabolism; D010003:Osteoarthritis / Q000201:enzymology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013295:Streptococcus mutans / Q000737:chemistry*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D001426:Bacterial Proteins; D004792:Enzyme Precursors; C496449:FGF5 protein, human; D039081:Integrin alpha5beta1; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008024:Ligands; D011993:Recombinant Fusion Proteins; C508943:protein I-II, Streptococcus mutans; D051521:Fibroblast Growth Factor 5; D019278:Matrix Metalloproteinase 3