Induction of matrix metalloproteinase 1 gene expression is regulated by inflammation-responsive transcription factor SAF-1 in osteoarthritis.
OBJECTIVE
To identify specific transcription factors that are activated in the cartilage tissue of osteoarthritis (OA) patients and are involved in the expression of matrix metalloproteinase 1 (MMP-1).


METHODS
DNase I footprint and electrophoretic mobility shift assays were performed to identify active elements of the MMP1 promoter and the transcription factors that interact with it. The relative abundance of the involved transcription factor in the cartilage was determined by immunohistochemical analysis. The role of serum amyloid A-activating factor 1 (SAF-1) in MMP-1 expression was assessed by transient transfection assay with plasmids containing either a functional or an antisense SAF-1 complementary DNA.


RESULTS
A novel promoter element was detected in the human MMP1 gene, and the inflammation-responsive transcription factor SAF-1 was found to interact with it. SAF-1 activity was detected in the chondrocytes of OA cartilage, where most of the cells stained positive for SAF-1. Overexpression of SAF-1 in OA chondrocytes increased the expression of the MMP1 promoter, and interference of endogenous SAF-1 activity by antisense SAF-1 messenger RNA inhibited interleukin-1-mediated MMP1 promoter activity.


CONCLUSIONS
The results indicate that SAF-1 is involved in the regulation of MMP1 gene expression and it is highly abundant in the articular cartilage chondrocytes of OA patients. The data also demonstrate that control of SAF-1 activity can suppress induced expression of MMP-1. Conceivably, SAF-1 could be a potential therapeutic target to control the overexpression of MMP-1 associated with the pathogenesis of OA.
Ray
Alpana
A
University of Missouri, Columbia 65211, USA.
Kuroki
Keiichi
K
Cook
James L
JL
Bal
B Sonny
BS
Kenter
Keith
K
Aust
Gabriela
G
Ray
Bimal K
BK
D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D004285:Dogs; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000235:genetics*; D010003:Osteoarthritis / Q000378:metabolism* / Q000503:physiopathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D014157:Transcription Factors; C076035:c-MYC-associated zinc finger protein; D020781:Matrix Metalloproteinase 1