title: Nicotinamide phosphoribosyltransferase is essential for interleukin-1beta-mediated dedifferentiation of articular chondrocytes via SIRT1 and extracellular signal-regulated kinase (ERK) complex signaling.
abstract: Although much is known about interleukin (IL)-1β and its role as a key mediator of cartilage destruction in osteoarthritis, only limited information is available on IL-1β signaling in chondrocyte dedifferentiation. Here, we have characterized the molecular mechanisms leading to the dedifferentiation of primary cultured articular chondrocytes by IL-1β treatment. IL-1β or lipopolysaccharide, but not phorbol 12-myristate 13-acetate, retinoic acid, or epidermal growth factor, induced nicotinamide phosphoribosyltransferase (NAMPT) expression, showing the association of inflammatory cytokines with NAMPT regulation. SIRT1, in turn, was activated NAMPT-dependently, without any alteration in the expression level. Activation or inhibition of SIRT1 oppositevely regulates IL-1β-mediated chondrocyte dedifferentiation, suggesting this protein as a key regulator of chondrocytes phenotype. SIRT1 activation promotes induction of ERK and p38 kinase activities, but not JNK, in response to IL-1β. Subsequently, ERK and p38 kinase activated by SIRT1 also induce SIRT1 activation, forming a positive feedback loop to sustain downstream signaling of these kinases. Moreover, we found that the SIRT1-ERK complex, but not SIRT1-p38, is engaged in IL-1β-induced chondrocyte dedifferentiation via a Sox-9-mediated mechanism. JNK is activated by IL-1β and modulates dedifferentiation of chondrocytes, but this pathway is independent on NAMPT-SIRT1 signaling. Based on these findings, we propose that IL-1β induces dedifferentiation of articular chondrocytes by up-regulation of SIRT1 activity enhanced by both NAMPT and ERK signaling.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Hong
authors.forename: Hong Shik
authors.initials: HS
authors.lastname: Yun
authors.forename: Jongdoo
authors.initials: J
authors.lastname: Kim
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Chang-Mo
authors.initials: CM
authors.lastname: Kang
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D016207:Cytokines; C508585:IL1B protein, human; D053583:Interleukin-1beta; D009097:Multienzyme Complexes; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D013755:Tetradecanoylphorbol Acetate