BACKGROUND: In the synovial membrane of patients with rheumatoid arthritis (RA), a strong expression of laminins and matrix degrading proteases was reported. AIM: To investigate the regulation of matrix metalloproteinases (MMPs) in synovial fibroblasts (SFs) of patients with osteoarthritis (OA) and RA by attachment to laminin-1 (LM-111) and in the presence or absence of costimulatory signals provided by transforming growth factor beta (TGFbeta). METHODS: SFs were seeded in laminin-coated flasks and activated by addition of TGFbeta. The expression of genes was investigated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunocytochemistry and ELISA, and intracellular signalling pathways by immunoblotting, and by poisoning p38MAPK by SB203580, MEK-ERK by PD98059 and SMAD2 by A-83-01. RESULTS: Attachment of SF to LM-111 did not activate the expression of MMPs, but addition of TGFbeta induced a fivefold higher expression of MMP-3. Incubation of SF on LM-111 in the presence of TGFbeta induced a significant 12-fold higher expression of MMP-3 mRNA, and secretion of MMP-3 was elevated 20-fold above controls. Functional blocking of LM-111-integrin interaction reduced the laminin-activated MMP-3 expression significantly. Stimulation of SF by LM-111 and TGFbeta activated the p38MAPK, ERK and SMAD2 pathways, and inhibition of these pathways by using SB203580, PD98059 or A-83-01 confirmed the involvement of these pathways in the regulation of MMP-3. CONCLUSION: Attachment of SF to LM-111 by itself has only minor effects on the expression of MMP-1 or MMP-3, but it facilitates the TGFbeta-induced expression of MMP-3 significantly. This mode of MMP-3 induction may therefore contribute to inflammatory joint destruction in RA independent of the proinflammatory cytokines interleukin (IL)1beta or tumour necrosis factor (TNF)alpha.
BACKGROUND: In the synovial membrane of patients with rheumatoid arthritis (RA), a strong expression of laminins and matrix degrading proteases was reported. AIM: To investigate the regulation of matrix metalloproteinases (MMPs) in synovial fibroblasts (SFs) of patients with osteoarthritis (OA) and RA by attachment to laminin-1 (LM-111) and in the presence or absence of costimulatory signals provided by transforming growth factor beta (TGFbeta). METHODS: SFs were seeded in laminin-coated flasks and activated by addition of TGFbeta. The expression of genes was investigated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunocytochemistry and ELISA, and intracellular signalling pathways by immunoblotting, and by poisoning p38MAPK by SB203580, MEK-ERK by PD98059 and SMAD2 by A-83-01. RESULTS: Attachment of SF to LM-111 did not activate the expression of MMPs, but addition of TGFbeta induced a fivefold higher expression of MMP-3. Incubation of SF on LM-111 in the presence of TGFbeta induced a significant 12-fold higher expression of MMP-3 mRNA, and secretion of MMP-3 was elevated 20-fold above controls. Functional blocking of LM-111-integrin interaction reduced the laminin-activated MMP-3 expression significantly. Stimulation of SF by LM-111 and TGFbeta activated the p38MAPK, ERK and SMAD2 pathways, and inhibition of these pathways by using SB203580, PD98059 or A-83-01 confirmed the involvement of these pathways in the regulation of MMP-3. CONCLUSION: Attachment of SF to LM-111 by itself has only minor effects on the expression of MMP-1 or MMP-3, but it facilitates the TGFbeta-induced expression of MMP-3 significantly. This mode of MMP-3 induction may therefore contribute to inflammatory joint destruction in RA independent of the proinflammatory cytokines interleukin (IL)1beta or tumour necrosis factor (TNF)alpha.
Authors: Y T Konttinen; T F Li; J W Xu; M Tagaki; L Pirilä; T Silvennoinen; S Santavirta; I Virtanen Journal: Ann Rheum Dis Date: 1999-11 Impact factor: 19.103
Authors: Tracy L Adair-Kirk; Jeffrey J Atkinson; Thomas J Broekelmann; Masayuki Doi; Karl Tryggvason; Jeffrey H Miner; Robert P Mecham; Robert M Senior Journal: J Immunol Date: 2003-07-01 Impact factor: 5.422
Authors: Peter A Mollica; Elizabeth N Booth-Creech; John A Reid; Martina Zamponi; Shea M Sullivan; Xavier-Lewis Palmer; Patrick C Sachs; Robert D Bruno Journal: Acta Biomater Date: 2019-06-21 Impact factor: 8.947