期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 40, 页码 28620-28629出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.452169
关键词
ADAM ADAMTS; Articular Cartilage; Cartilage; Cartilage Biology; Chondrocytes; NF-kappa B (NF-KB); Osteoarthritis; Transcription; ADAMTS5; RelA; p65
资金
- Japanese Ministry of Education, Culture, Sports, Science and Technology [24592253, 22659266, 24659663]
- Grants-in-Aid for Scientific Research [24592253, 25293316, 23689065, 24659663, 25253087, 22659266, 25670634] Funding Source: KAKEN
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-B family member RelA/p65 most strongly stimulated the promoter activity. In the ADAMTS5 gene, there were three NF-B 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.
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