title: The NAD-Dependent Deacetylase Sirtuin-1 Regulates the Expression of Osteogenic Transcriptional Activator Runt-Related Transcription Factor 2 (Runx2) and Production of Matrix Metalloproteinase (MMP)-13 in Chondrocytes in Osteoarthritis.
abstract: Aging is one of the major pathologic factors associated with osteoarthritis (OA). Recently, numerous reports have demonstrated the impact of sirtuin-1 (Sirt1), which is the NAD-dependent deacetylase, on human aging. It has been demonstrated that Sirt1 induces osteogenic and chondrogenic differentiation of mesenchymal stem cells. However, the role of Sirt1 in the OA chondrocytes still remains unknown. We postulated that Sirt1 regulates a hypertrophic chondrocyte lineage and degeneration of articular cartilage through the activation of osteogenic transcriptional activator Runx2 and matrix metalloproteinase (MMP)-13 in OA chondrocytes. To verify whether sirtuin-1 (Sirt1) regulates chondrocyte activity in OA, we studied expressions of Sirt1, Runx2 and production of MMP-13, and their associations in human OA chondrocytes. The expression of Sirt1 was ubiquitously observed in osteoarthritic chondrocytes; in contrast, Runx2 expressed in the osteophyte region in patients with OA and OA model mice. OA relating catabolic factor IL-1βincreased the expression of Runx2 in OA chondrocytes. OA chondrocytes, which were pretreated with Sirt1 inhibitor, inhibited the IL-1β-induced expression of Runx2 compared to the control. Since the Runx2 is a promotor of MMP-13 expression, Sirt1 inactivation may inhibit the Runx2 expression and the resultant down-regulation of MMP-13 production in chondrocytes. Our findings suggest thatSirt1 may regulate the expression of Runx2, which is the osteogenic transcription factor, and the production of MMP-13 from chondrocytes in OA. Since Sirt1 activity is known to be affected by several stresses, including inflammation and oxidative stress, as well as aging, SIRT may be involved in the development of OA.
authors.affiliation: Department of Sports Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan. koh.seikei@marianna-u.ac.jp.
authors.forename: Koh
authors.initials: K
authors.lastname: Terauchi
authors.affiliation: Department of Sports Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan. h4kobayashi@marianna-u.ac.jp.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Sports Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan. kanaka@marianna-u.ac.jp.
authors.forename: Kanaka
authors.initials: K
authors.lastname: Yatabe
authors.affiliation: Department of Sports Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan. aburainisuke@marianna-u.ac.jp.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yui
authors.affiliation: Department of Sports Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan. fujiya-1487@marianna-u.ac.jp.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Fujiya
authors.affiliation: Department of Orthopaedic Surgery, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8512, Japan. h2niki@marianna-u.ac.jp.
authors.forename: Hisateru
authors.initials: H
authors.lastname: Niki
authors.affiliation: Department of Sports Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan. musha@marianna-u.ac.jp.
authors.forename: Haruki
authors.initials: H
authors.lastname: Musha
authors.affiliation: Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8512, Japan. yudo@marianna-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yudoh
mesh_terms: D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; C493709:RUNX2 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: NAD-dependent deacetylase; Runx2; chondrocytes; osteoarthritis; sirtuin