OBJECTIVE: To investigate the regulatory potential of early growth response 1 (Egr-1) on tissue inhibitor of metalloproteinases 1 (TIMP-1) expression in synovial fibroblasts. METHODS: Egr-1 and TIMP-1 transcripts were detected by in situ hybridization in synovial tissue. Egr-1-regulated TIMP expression was studied in immortalized fibroblast lines using gel retardation assays, RNase protection analysis, reporter gene studies using the human TIMP-1 promoter, and by enzyme-linked immunosorbent assay. RESULTS: TIMP-1 and Egr-1 were coexpressed in synovial fibroblasts of inflamed joints, and Egr-1 activated the expression of TIMP-1. Egr-1 binding to a recognition sequence in the TIMP-1 promoter was demonstrated in gel retardation and reporter gene assays. Since the same DNA sequence was also recognized by the transcription factor Sp-1, our results suggest that the expression of TIMP-1 in synovial fibroblasts may be differentially regulated by Egr-1 and Sp-1. In addition, fibroblasts expressing Egr-1 at high levels were found to express increased levels of TIMP-2 and TIMP-3 messenger RNA. CONCLUSION: The enhanced expression of Egr-1 may regulate the activity of matrix metalloproteinases in synovial fibroblasts by enhancing the expression of the TIMP-1, -2, and -3 genes.
OBJECTIVE: To investigate the regulatory potential of early growth response 1 (Egr-1) on tissue inhibitor of metalloproteinases 1 (TIMP-1) expression in synovial fibroblasts. METHODS:Egr-1 and TIMP-1 transcripts were detected by in situ hybridization in synovial tissue. Egr-1-regulated TIMP expression was studied in immortalized fibroblast lines using gel retardation assays, RNase protection analysis, reporter gene studies using the humanTIMP-1 promoter, and by enzyme-linked immunosorbent assay. RESULTS:TIMP-1 and Egr-1 were coexpressed in synovial fibroblasts of inflamed joints, and Egr-1 activated the expression of TIMP-1. Egr-1 binding to a recognition sequence in the TIMP-1 promoter was demonstrated in gel retardation and reporter gene assays. Since the same DNA sequence was also recognized by the transcription factor Sp-1, our results suggest that the expression of TIMP-1 in synovial fibroblasts may be differentially regulated by Egr-1 and Sp-1. In addition, fibroblasts expressing Egr-1 at high levels were found to express increased levels of TIMP-2 and TIMP-3 messenger RNA. CONCLUSION: The enhanced expression of Egr-1 may regulate the activity of matrix metalloproteinases in synovial fibroblasts by enhancing the expression of the TIMP-1, -2, and -3 genes.
Authors: Maik Hoberg; Maximilian Rudert; Thomas Pap; Gerd Klein; Steffen Gay; Wilhelm K Aicher Journal: Ann Rheum Dis Date: 2006-11-23 Impact factor: 19.103
Authors: M A Friese; T Manuelian; S Junnikkala; J Hellwage; S Meri; H H Peter; D L Gordon; H Eibel; P F Zipfel Journal: Clin Exp Immunol Date: 2003-06 Impact factor: 4.330