title: The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin-1β in human chondrocytes.
abstract: In this study, we examined the effects of overexpression of SIRT1 on IL-1β-induced gene expression changes in human chondrocytes to explore a protective role of SIRT1 in human chondrocytes. SIRT1 was overexpressed in human chondrocytes by expression plasmid under stimulation with IL-1β. SIRT1 was also inhibited by siRNA under stimulation with IL-1β. Gene expression changes were examined by real-time PCR. The interaction of SIRT1 and p65 (NF-κB) were examined by Western blotting. SIRT1, MMP-13, and ADAMTS-5 expressions in human cartilage were examined by immunohistochemistry. IL-1β stimulation significantly up-regulated MMP-1, 2, 9, and 13 and ADAMTS-5. Overexpression of SIRT1 significantly inhibited the up-regulation of those genes caused by IL-1β while the inhibition of SIRT1 further increased them. In addition, the overexpression of SIRT1 markedly reduced the IL-1β-induced acetylation of p65. SIRT1 expression was clearly detected in the non-OA cartilage while MMP-13 and ADAMTS-5 were undetectable. In contrast, in the OA cartilage, SIRT1 expression was decreased while MMP-13 and ADAMTS-5 were increased. Our observations suggested that SIRT1 can play a protective role by suppressing IL-1β-induced expressions of cartilage-degrading enzymes partially through the modulation of the NF-κB pathway. SIRT1 overexpression might be a new therapeutic approach for OA.
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. matsushi@med.kobe-u.ac.jp
authors.forename: Takehiko
authors.initials: T
authors.lastname: Matsushita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Koji
authors.initials: K
authors.lastname: Takayama
authors.forename: Kazunari
authors.initials: K
authors.lastname: Ishida
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Kubo
authors.forename: Tokio
authors.initials: T
authors.lastname: Matsuzaki
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nishida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis; D000071116:ADAMTS5 Protein; D002358:Cartilage, Articular / Q000378:metabolism*; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D010003:Osteoarthritis / Q000378:metabolism*; D056564:Sirtuin 1 / Q000096:biosynthesis*; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D051996:Transcription Factor RelA; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D020782:Matrix Metalloproteinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1