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: Judith Sylvester, Rasheed Ahmad, Muhammad Zafarullah
• Journal: Rheumatology international (Rheumatol Int) Vol. 33 Issue 2 Pg. 517-22 (Feb 2013) ISSN: 1437-160X [Electronic] Germany
• PMID: 22065068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• RNA, Messenger
• Sp1 Transcription Factor
• WP 631
• ADAM Proteins
• Procollagen N-Endopeptidase
• ADAMTS4 Protein
• ADAMTS4 protein, human
• Plicamycin
• Daunorubicin

Topics

• ADAM Proteins (genetics)
• ADAMTS4 Protein
• Cartilage, Articular (cytology, metabolism)
• Cells, Cultured
• Chondrocytes (metabolism)
• Daunorubicin (analogs & derivatives, pharmacology)
• Humans
• Interleukin-1beta (pharmacology)
• Plicamycin (pharmacology)
• Procollagen N-Endopeptidase (genetics)
• RNA, Messenger (analysis)
• Sp1 Transcription Factor (physiology)