title: Catabolic stress induces features of chondrocyte senescence through overexpression of caveolin 1: possible involvement of caveolin 1-induced down-regulation of articular chondrocytes in the pathogenesis of osteoarthritis.
abstract: OBJECTIVE
  Articular chondrocyte senescence is responsible, at least in part, for the increased incidence of osteoarthritis (OA) with increased age. Recently, it was suggested that caveolin 1, a 21-24-kd membrane protein, participates in premature cellular senescence. Caveolin 1 is the principal structural component of caveolae, vesicular invaginations of the plasma membrane. This study was undertaken to investigate whether the catabolic factors oxidative stress and interleukin-1beta (IL-1beta) induce features of premature senescence of articular chondrocytes through up-regulation of caveolin 1 expression.
  
  
  METHODS
  Caveolin 1 expression was investigated in human OA cartilage by real-time polymerase chain reaction and in rat OA cartilage by immunohistologic analysis. We studied whether IL-1beta and H2O2 induce caveolin 1 expression in OA chondrocytes and analyzed the relationship between cellular senescent phenotypes and caveolin 1 expression in human chondrocytes.
  
  
  RESULTS
  In human and rat OA articular cartilage, caveolin 1 positivity was associated with cartilage degeneration. Both IL-1beta and H2O2 up-regulated caveolin 1 messenger RNA and protein levels, and both treatments induced marked expression of senescent phenotypes: altered cellular morphology, cell growth arrest, telomere erosion, and specific senescence-associated beta-galactosidase activity. Caveolin 1 overexpression induced p38 MAPK activation and impaired the ability of chondrocytes to produce type II collagen and aggrecan. In contrast, down-regulation of caveolin 1 with antisense oligonucleotide significantly inhibited the features of chondrocyte senescence induced by catabolic factors. Caveolin 1 induction and stresses with both IL-1beta and H2O2 up-regulated p53 and p21 and down-regulated phosphorylated retinoblastoma (Rb), suggesting that the p53/p21/Rb phosphorylation pathway, as well as prolonged p38 MAPK activation, may mediate the features of chondrocyte senescence induced by stress.
  
  
  CONCLUSIONS
  Our findings suggest that IL-1beta and oxidative stress induce features of premature senescence in OA chondrocytes, mediated, at least in part, by stress-induced caveolin 1 expression. This indicates that caveolin 1 plays a role in the pathogenesis of OA via promotion of chondrocyte down-regulation.
authors.affiliation: St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Sheng-Ming
authors.initials: SM
authors.lastname: Dai
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Shan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Kayo
authors.initials: K
authors.lastname: Masuko-Hongo
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kato
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yudoh
mesh_terms: D053674:Aggrecans; D000818:Animals; D002358:Cartilage, Articular / Q000502:physiology*; D051242:Caveolin 1 / Q000032:analysis* / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D019902:Chondrocytes / Q000737:chemistry / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000032:analysis; D024043:Collagen Type II / Q000096:biosynthesis; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000032:analysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type / Q000032:analysis; D008297:Male; D010003:Osteoarthritis / Q000209:etiology*; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016615:Telomere; D001616:beta-Galactosidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508321:Acan protein, rat; D053674:Aggrecans; D051242:Caveolin 1; D011508:Chondroitin Sulfate Proteoglycans; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase