title: Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis.
abstract: OBJECTIVE
  The zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis.
  
  
  METHODS
  Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL).
  
  
  RESULTS
  MTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA.
  
  
  CONCLUSIONS
  MTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Yoonkyung
authors.initials: Y
authors.lastname: Won
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Youngnim
authors.initials: Y
authors.lastname: Shin
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: Department of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Yongsik
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, SungKyunKwan University School of Medicine, Seoul, Korea Department of Health Sciences and Technology, SAIHST, SungKyunKwan University, Seoul, South Korea.
authors.forename: Chul-Won
authors.initials: CW
authors.lastname: Ha
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea Department of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001169:Arthritis, Experimental / Q000235:genetics* / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D058685:Genetic Pleiotropy; D006801:Humans; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D008668:Metallothionein
keywords: Arthritis; Chondrocytes; Osteoarthritis