Open AccessTranscription factor early growth response 1 activity up‐regulates expression of tissue inhibitor of metalloproteinases 1 in human synovial fibroblasts
Author(s) -
Aicher Wilhelm K.,
Alexander Dorothea,
Haas Christian,
Kuchen Stefan,
Pagenstecher Axel,
Gay Steffen,
Peter HansHartmut,
Eibel Hermann
Publication year - 2003
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.10774
Subject(s) - microbiology and biotechnology , matrix metalloproteinase , fibroblast , gene expression , reporter gene , biology , messenger rna , transcription factor , tissue inhibitor of metalloproteinase , transcription (linguistics) , promoter , synovial membrane , in situ hybridization , gene , chemistry , cell culture , immunology , inflammation , biochemistry , genetics , linguistics , philosophy
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.