Transcriptional Induction of ADAMTS5 Protein by Nuclear Factor-κB (NF-κB) Family Member RelA/p65 in Chondrocytes during Osteoarthritis Development*

Background: ADAMTS5 is a crucial proteinase for osteoarthritis development. Results: NF-κB family member RelA/p65 was identified as a potent transactivator of ADAMTS5 and regulated the expression and aggrecanolysis. Conclusion: RelA/p65 is a potent transcriptional activator of ADAMTS5 in chondrocytes during osteoarthritis development. Significance: The molecular network related to the RelA/p65-ADAMTS5 axis may represent a therapeutic target for osteoarthritis. Here we sought to identify transcription factors that induce ADAMTS5, a crucial proteinase for osteoarthritis development. Exhaustive comparison of the genomic sequences of human, macaque, and mouse ADAMTS5 genes revealed that the proximal 1.4 kb of the 5′-end-flanking regions containing several consensus motifs was highly conserved. Among putative transcription factors for these motifs, NF-κB family member RelA/p65 most strongly stimulated the promoter activity. In the ADAMTS5 gene, there were three NF-κB binding motifs, in which deletion, mutagenesis, and tandem repeat analyses of the luciferase assay identified the core responsive elements of RelA/p65 to be −896/−887 and −424/−415 bp with specific bindings. The endogenous Adamts5 expression in ATDC5 cells was increased by RelA/p65 overexpression and decreased by knockdown through its siRNA. The expression was also inhibited by the Rela deletion through Cre transfection in primary articular chondrocytes from Relafl/fl mice. In the ex vivo culture of femoral head cartilage from mesenchymal cell-specific Rela knock-out (Prx1-Cre;Relafl/fl) mice, aggrecanolysis was significantly lower than that in the Relafl/fl cartilage. Finally, in the experimental mouse osteoarthritis model, ADAMTS5 and RelA were co-localized in chondrocytes of degraded articular cartilage. We conclude that RelA/p65 is a potent transcriptional activator of ADAMTS5 in chondrocytes during osteoarthritis development.

• Publication year

  2013

• Venue

  Journal of Biological Chemistry

• Publication date

  2013-08-20

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M113.452169PMID 23963448PMCID PMC3789961
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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