Role of Sp1 transcription factor in Interleukin-1-induced ADAMTS-4 (aggrecanase-1) gene expression in human articular chondrocytes

Judith Sylvester, Rasheed Ahmad, Muhammad Zafarullah

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)517-522
Number of pages6
JournalRheumatology International
Volume33
Issue number2
DOIs
Publication statusPublished - 1 Feb 2013

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Keywords

  • Aggrecanase (ADAMTS-4)
  • Cartilage
  • Inhibition
  • Interleukin-1 (IL-1)
  • Regulation
  • Specificity protein-1 (Sp1)

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