title: NAMPT (visfatin), a direct target of hypoxia-inducible factor-2α, is an essential catabolic regulator of osteoarthritis.
abstract: OBJECTIVE
  Hypoxia-inducible factor 2α (HIF-2α), encoded by Epas1, causes osteoarthritic cartilage destruction by regulating the expression of matrix-degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2α-mediated osteoarthritic cartilage destruction.
  
  
  METHODS
  The expression of HIF-2α, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad-Epas1 or Ad-Nampt in wild-type, Epas1(+/-), Epas1(fl/fl);Col2a1-Cre and Col2a1-Nampt transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses.
  
  
  RESULTS
  We found that the Nampt gene is a direct target of HIF-2α in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2α-induced expression of catabolic enzymes. Gain-of-function studies (intra-articular injection of Ad-Nampt; Col2a1-Nampt TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.
  
  
  CONCLUSIONS
  Our findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2α, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Siyoung
authors.initials: S
authors.lastname: Yang
authors.affiliation: Research Center for Biomineralization Disorders and Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea.
authors.forename: Je-Hwang
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Hwanhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Jimin
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Kwak
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Hallym University Sacred Heart Hospital, Kyunggi, Korea.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Kim
authors.affiliation: Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Korea.
authors.forename: Churl-Hong
authors.initials: CH
authors.lastname: Chun
authors.affiliation: Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism*; D024043:Collagen Type II / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D053674:Aggrecans; D051792:Basic Helix-Loop-Helix Proteins; D024043:Collagen Type II; D020782:Matrix Metalloproteinases; D054409:Nicotinamide Phosphoribosyltransferase; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: Chondrocytes; Cytokines; Knee Osteoarthritis; Osteoarthritis; Synovitis