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

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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.

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Acknowledgments

This work was supported by the Canadian Institutes of Health Research (CIHR) grant MOP-57848.

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Authors and Affiliations

  1. Centre de Recherche du CHUM (CRCHUM), Notre-Dame Hospital, University of Montreal, 1560 Sherbrooke E, Montreal, QC, H2L 4M1, Canada

    Judith Sylvester & Rasheed Ahmad

  2. Department of Medicine, University of Montreal and Centre de Recherche du CHUM (CRCHUM), Hôpital Notre-Dame du CHUM, K-5255 Mailloux, 1560 Sherbrooke est, Montréal, QC, H2L 4M1, Canada

    Muhammad Zafarullah

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  1. Judith Sylvester
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Correspondence to Muhammad Zafarullah.

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Sylvester, J., Ahmad, R. & Zafarullah, M. Role of Sp1 transcription factor in Interleukin-1-induced ADAMTS-4 (aggrecanase-1) gene expression in human articular chondrocytes. Rheumatol Int 33, 517–522 (2013). https://doi.org/10.1007/s00296-011-2187-1

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