Transcription factor early growth response 1 activity up-regulates expression of tissue inhibitor of metalloproteinases 1 in human synovial fibroblasts

Arthritis Rheum. 2003 Feb;48(2):348-59. doi: 10.1002/art.10774.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / physiopathology
  • Binding Sites / genetics
  • Cell Line, Transformed
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Early Growth Response Protein 1
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Regulation / physiology
  • Humans
  • Immediate-Early Proteins*
  • Promoter Regions, Genetic / physiology
  • Synovial Membrane / cytology*
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Tissue Inhibitor of Metalloproteinase-3 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism
  • Tissue Inhibitor of Metalloproteinase-4
  • Tissue Inhibitor of Metalloproteinases / genetics
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transfection
  • Up-Regulation / physiology

Substances

  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Immediate-Early Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-3
  • Tissue Inhibitor of Metalloproteinases
  • Transcription Factors
  • Tissue Inhibitor of Metalloproteinase-2