title: Role of Sp1 transcription factor in Interleukin-1-induced ADAMTS-4 (aggrecanase-1) gene expression in human articular chondrocytes.
abstract: Proinflammatory cytokines such as interleukin-1 beta (IL-1β) stimulate cartilage extracellular matrix aggrecan degradation by aggrecanases or ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) during the pathogenesis of arthritis. Human aggrecanase-1 (ADAMTS-4) gene promoter contains at least one specificity protein-1 (Sp1)-transcription factor-binding site. We investigated the previously unknown role of Sp1 in the regulation of ADAMTS-4 gene expression in human articular chondrocytes. Mithramycin and WP631, the specific inhibitors of guanine cytosine (GC)-rich Sp1 DNA binding, partially suppressed IL-1-induced ADAMTS-4 expression and activity. Genetic inhibition of Sp1 by antisense oligonucleotide or by small interfering RNA (siRNA)-mediated Sp1 knockdown partially inhibited ADAMTS-4 induction by IL-1. Sense oligonucleotide and negative control siRNA had no effect. In contrast, cytomegalovirus promoter-driven Sp1 overexpression further enhanced IL-1-induced ADAMTS-4 expression and activity. Constitutively expressed glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was not affected by any of the agents. These results provide pharmacological and genetic evidence for the importance of Sp1 in ADAMTS-4 gene regulation by IL-1. Thus, Sp1 could be potentially targeted to reduce arthritis-associated cartilage aggrecan loss.
authors: Centre de Recherche du CHUM, Notre-Dame Hospital, University of Montreal, 1560 Sherbrooke E, Montreal, QC H2L 4M1, Canada.
authors: Judith
authors: J
authors: Sylvester
authors: Rasheed
authors: R
authors: Ahmad
authors: Muhammad
authors: M
authors: Zafarullah
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071121:ADAMTS4 Protein; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D008926:Plicamycin / Q000494:pharmacology; D011348:Procollagen N-Endopeptidase / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D016329:Sp1 Transcription Factor / Q000502:physiology*
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C104426:WP 631; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; D008926:Plicamycin; D003630:Daunorubicin