| First Author | Kobayashi H | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 40 | Pages | 28620-9 |
| PubMed ID | 23963448 | Mgi Jnum | J:203959 |
| Mgi Id | MGI:5529227 | Doi | 10.1074/jbc.M113.452169 |
| Citation | Kobayashi H, et al. (2013) Transcriptional induction of ADAMTS5 protein by nuclear factor-kappaB (NF-kappaB) family member RelA/p65 in chondrocytes during osteoarthritis development. J Biol Chem 288(40):28620-9 |
| abstractText | 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-kappaB family member RelA/p65 most strongly stimulated the promoter activity. In the ADAMTS5 gene, there were three NF-kappaB 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 Rela(fl/fl) mice. In the ex vivo culture of femoral head cartilage from mesenchymal cell-specific Rela knock-out (Prx1-Cre;Rela(fl/fl)) mice, aggrecanolysis was significantly lower than that in the Rela(fl/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. |
