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


CONCLUSIONS
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.
Aicher
Wilhelm K
WK
University Hospital Tubingen, Tubingen, Germany.
Alexander
Dorothea
D
Haas
Christian
C
Kuchen
Stefan
S
Pagenstecher
Axel
A
Gay
Steffen
S
Peter
Hans-Hartmut
HH
Eibel
Hermann
H
D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000503:physiopathology; D001665:Binding Sites / Q000235:genetics; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins; D011401:Promoter Regions, Genetic / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology; D000097792:Tissue Inhibitor of Metalloproteinase-4
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D014157:Transcription Factors; D000097792:Tissue Inhibitor of Metalloproteinase-4; C497325:EGR1 protein, human