title: Transcriptional induction of ADAMTS5 protein by nuclear factor-κB (NF-κB) family member RelA/p65 in chondrocytes during osteoarthritis development.
abstract: 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 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.
authors: From the Departments of Sensory and Motor System Medicine and.
authors: Hiroshi
authors: H
authors: Kobayashi
authors: Makoto
authors: M
authors: Hirata
authors: Taku
authors: T
authors: Saito
authors: Shozo
authors: S
authors: Itoh
authors: Ung-il
authors: UI
authors: Chung
authors: Hiroshi
authors: H
authors: Kawaguchi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071116:ADAMTS5 Protein; D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D019902:Chondrocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008251:Macaca; D051379:Mice; D008969:Molecular Sequence Data; D010003:Osteoarthritis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D053674:Aggrecans; D015534:Trans-Activators; D051996:Transcription Factor RelA; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; C498489:Adamts5 protein, mouse
keywords: ADAM ADAMTS; ADAMTS5; Articular Cartilage; Cartilage; Cartilage Biology; Chondrocytes; NF-kappa B (NF-KB); Osteoarthritis; RelA/p65; Transcription
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