Coordinate regulation of matrix metalloproteases and tissue inhibitor of metalloproteinase expression in human synovial fibroblasts.
We examined the common signal transduction mechanisms governing collagenase (MMP-1), stromelysin-1 (MMP-3), and tissue inhibitor of metalloproteases (TIMP-1) gene expression in human synovial fibroblasts for insight into the pathophysiology of arthritis. MMP-1, MMP-3, and TIMP-1 expression and synthesis were induced in cultured human synoviocytes with recombinant human interleukin 1 beta in the absence or presence of either chemical inhibitors of protein kinase A and C (PKA, PKC), or prostaglandin E2, or cyclic AMP (cAMP) mimetics. We used enzyme immunoassays (EIA) to determine MMP-1, MMP-3, and TIMP-1 antigen levels in spent culture medium and Northern hybridization to measure steady state mRNA expression levels. Extracellular signals (e.g., IL-1, phorbol myristic acetate) that result in the activation of cytoplasmic PKC augment in tandem the expression and synthesis of MMP-1, MMP-3, and TIMP-1 in human synovial fibroblasts. In addition, such signals induce nuclear transcription factors (e.g., activator protein 1) that bind to common gene regulatory elements and augment promoter activity of MMP-1, MMP-3, and TIMP-1 gene promoter constructs. In contrast, signals that activate PKA oppose PKC mediated signals, in that the expression of MMP-1, MMP-3, and TIMP-1 are suppressed. Experimental data suggest that the expression of MMP-1, MMP-3, and TIMP-1 are coordinated through a series of common cytoplasmic signal transducing pathways, cis regulatory elements, and nuclear trans acting factors.
DiBattista
J A
JA
Louis-Charles Simard Research Center, Notre-Dame Hospital, Department of Medicine, University of Montreal, PQ, Canada.
Pelletier
J P
JP
Zafarullah
M
M
Fujimoto
N
N
Obata
K
K
Martel-Pelletier
J
J
D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis* / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000187:drug effects; D011494:Protein Kinases / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D007375:Interleukin-1; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D011494:Protein Kinases; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone