COORDINATE REGULATION OF MATRIX METALLOPROTEASES AND TISSUE INHIBITOROF METALLOPROTEINASE EXPRESSION IN HUMAN SYNOVIAL FIBROBLASTS

We examined the common signal transduction mechanisms governing collag enase (MMP-1), stromelysin-l (MMP-3), and tissue inhibitor of metallop roteases (TIMP-1) gene expression in human synovial fibroblasts for in sight into the pathophysiology of arthritis. MMP-1, MMP-3, and TIMP-1 expression and synthesis were induced in cultured human synoviocytes w ith recombinant human interleukin 1 beta in the absence or presence of either chemical inhibitors of protein kinase A and C (PKA, PKC), or p rostaglandin E(2), or cyclic AMP (cAMP) mimetics. We used enzyme immun oassays (EIA) to determine MMP-1, MMP-3, and TIMP-1 antigen levels in spent culture medium and Northern hybridization to measure steady stat e mRNA expression levels. Extracellular signals (e.g., IL-1, phorbol m yristic acetate) that result in the activation of cytoplasmic PKC augm ent in tandem the expression and synthesis of MMP-1, MMP-3, and TIMP-1 in human synovial fibroblasts. In addition, such signals induce nucle ar transcription factors (e.g., activator protein 1) that bind to comm on gene regulatory elements and augment promoter activity of MMP-1, MM P-3, and TIMP-1 gene promoter constructs. In contrast, signals that ac tivate PKA oppose PKC mediated signals, in that the expression of MMP- 1, MMP-3, and TIMP-1 are suppressed. Experimental data suggest that th e expression of MMP-1, MMP-3, and TIMP-1 are coordinated through a ser ies of common cytoplasmic signal transducing pathways, cia regulatory elements, and nuclear trans acting factors.