THE NUCLEAR RECEPTOR COREPRESSOR SMRT INHIBITS INTERSTITIAL COLLAGENASE (MMP-1) TRANSCRIPTION THROUGH AN HRE-INDEPENDENT MECHANISM

Nuclear receptors inhibit synthesis of collagenase-1 (matrix metallopr oeinase-1; MMP-1), an enzyme that degrades interstitial collagens and contributes to joint pathology in rheumatoid arthritis, SMRT (Silencin g Mediator for Retinoid and Thyroid hormone receptors) mediates the re pressive effect of nuclear receptors at hormone responsive elements (H REs), prompting us to investigate whether this co-repressor could also regulate transcription of MMP-1, which lacks any known HREs. We find that primary synovial fibroblasts express SMRT, When over-expressed by transient transfection, SMRT inhibits MMP-1 promoter activity induced by interleukin-1 (IL-1), phorbol phorbol myristate acetate (PMA) or v -Src, SMRT apparently inhibits MMP-1 gene expression by interfering wi th one or more transcriptional elements clustered in a region between -321 and +63. We conclude that SMRT negatively regulates MMP-1 synthes is through a novel, HRE-independent mechanism that involves proximal r egions of the MMP-1 promoter. (C) 1997 Academic Press.