title: Transcriptional induction of matrix metalloproteinase-9 in the chondrocyte and synoviocyte cells is regulated via a novel mechanism: evidence for functional cooperation between serum amyloid A-activating factor-1 and AP-1.
abstract: Increased expression of matrix metalloproteinase-9 (MMP-9) by IL-1beta and TNF-alpha is regarded as a key factor in the degradation of cartilage during arthritis. However, the underlying molecular mechanism of this induction process especially in the cells of the joint capsule remains elusive. Chondrocytes and synoviocytes, the resident cells of joint capsule, markedly increase transcription of MMP-9 in response to IL-1beta- and TNF-alpha-mediated stimulation. Using progressively deleted and mutant promoter constructs of MMP-9, we show that serum amyloid A-activating factor (SAF)-1, a novel transcription factor, and the AP-1 family of proteins cooperatively regulate cytokine-mediated induction of MMP-9 in the resident cells of the joint capsule. In the MMP-9 promoter, SAF-1 and AP-1 DNA-binding elements are present in close proximity with only 14 nucleotides apart. SAF-1 DNA-binding activity is increased in both cytokine-stimulated cells as well as in osteoarthritic cartilage tissues. Although overexpression of SAF-1 could increase expression of the MMP-9 promoter and endogenous MMP-9 gelatinolytic activity, for maximal induction of MMP-9 gene concurrent participation of SAF-1 and AP-1 is required. Mutation of either one of these two elements resulted in a severe reduction in cytokine responsiveness of MMP-9 promoter and compromised the transactivation potential of both SAF-1 and AP-1. Simultaneous requirement for two distinct DNA-binding elements suggests that SAF-1 and AP-1 function in a mutually beneficial manner acting as essential coactivators to drive cytokine-mediated transcriptional activation of MMP-9.
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, USA. rayal@missouri.edu
authors.forename: Alpana
authors.initials: A
authors.lastname: Ray
authors.forename: B Sonny
authors.initials: BS
authors.lastname: Bal
authors.forename: Bimal K
authors.initials: BK
authors.lastname: Ray
mesh_terms: D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000473:pathology; D002358:Cartilage, Articular / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D019902:Chondrocytes / Q000201:enzymology / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004285:Dogs; D005786:Gene Expression Regulation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D009154:Mutation; D011817:Rabbits; D013583:Synovial Membrane / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C076035:c-MYC-associated zinc finger protein; D020780:Matrix Metalloproteinase 9