MMP-3 expression and release by rheumatoid arthritis fibroblast-like synoviocytes induced with a bacterial ligand of integrin α5β1

Abstract

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 α5β1, 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 MMPfamily 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 α5β1 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.

MicroRNA-101-3p inhibits fibroblast-like synoviocyte proliferation and inflammation in rheumatoid arthritis by targeting PTGS2

“…More importantly, the findings revealed that up-regulation of miR-101-3p and down-regulation of PTGS2 led to diminished proliferation, migration, and invasion of FLSs, coupled with accelerated apoptosis. Accumulating studies have proved the association of FLSs with the pathogenesis of RA through producing effector molecules, thereby expediting the inflammation and joint damage [38,39]. Resistance to apoptosis of FLSs in RA is common in the inflamed joint as a prominent characteristic [9].…”

Matrix metalloproteinase-3 and the 7-joint ultrasound score in the assessment of disease activity and therapeutic efficacy in patients with moderate to severe rheumatoid arthritis

“…Houseman et al found that MMP-3 and anti-cyclic citrullinated peptide (anti-CCP) antibodies were strongly predictive of joint damage in patients with RA [ 5 ]. In addition, it was previously reported that MMP-3 levels in the synovium of patients with RA were significantly elevated; moreover, the gene that encodes MMP-3 was found to be overexpressed in the synovium [ 6 ]. These data suggest that MMP-3 is a biomarker of cartilage degeneration.…”

Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis

“…Integrin-linked activation of Rho GTPases mediates gene transcription, cell cycle progression and adhesion [ 13 , 15 ]. Previous studies have demonstrated that integrin blockade can inhibit fibroblast invasion and adhesion of cells to the extracellular matrix (ECM) [ 16 , 17 ]. In particular, blockade of α2β1 integrin in RA protects against cartilage destruction via reduction of matrix metalloproteinase (MMP)-3 [ 18 ].…”