title: Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C/EBP homologous protein.
abstract: OBJECTIVE
  When endoplasmic reticulum (ER) stress, i.e., the excessive accumulation of unfolded proteins in ER, endangers homeostasis, apoptosis is induced by C/EBP homologous protein (Chop). In osteoarthritis (OA) cartilage, Chop expression and apoptosis increase as degeneration progresses. We investigated the role of Chop in murine chondrocyte apoptosis and in the progression of cartilage degeneration.
  
  
  METHODS
  We induced experimental OA in Chop-knockout (Chop(-/-)) mice by medial collateral ligament transection and meniscectomy and compared cartilage degeneration, apoptosis, and ER stress in Chop(-/-)- and wild-type (Chop(+/+)) mice. In our in vitro experiments we treated murine Chop(-/-) chondrocytes with the ER stress inducer tunicamycin (TM) and evaluated apoptosis, ER stress, and chondrocyte function.
  
  
  RESULTS
  In vivo, the degree of ER stress was similar in Chop(-/-)- and Chop(+/+) mice. However, in Chop(-/-) mice apoptosis and cartilage degeneration were lower by 26.4% and 42.4% at 4 weeks, by 26.8% and 44.9% at 8 weeks, and by 26.9% and 32.3% at 12 weeks after surgery than Chop(+/+) mice, respectively. In vitro, the degree of ER stress induction by TM was similar in Chop(-/-)- and Chop(+/+) chondrocytes. On the other hand, apoptosis was 55.3% lower and the suppression of collagen type II and aggrecan mRNA was 21.0% and 23.3% less, and the increase of matrix metalloproteinase-13 mRNA was 20.0% less in Chop(-/-)- than Chop(+/+) chondrocytes.
  
  
  CONCLUSIONS
  Our results indicate that Chop plays a direct role in chondrocyte apoptosis and that Chop-mediated apoptosis contributes to the progression of cartilage degeneration in mice.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: ue1nen@yahoo.co.jp.
authors.forename: Y
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Orthopaedic Surgery, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: hirojun-mk@umin.ac.jp.
authors.forename: J
authors.initials: J
authors.lastname: Hirose
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: soichiro_yamabe@yahoo.co.jp.
authors.forename: S
authors.initials: S
authors.lastname: Yamabe
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: nobuoka9999@fc.kuh.kumamoto-u.ac.jp.
authors.forename: N
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: tatsuya-okada@fc.kuh.kumamoto-u.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.affiliation: Division of Molecular Biology, Institute for Genome Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Electronic address: oyadomar@genome.tokushima-u.ac.jp.
authors.forename: S
authors.initials: S
authors.lastname: Oyadomari
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: mizuta@kumamoto-u.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Mizuta
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002357:Cartilage Diseases / Q000473:pathology* / Q000503:physiopathology*; D002358:Cartilage, Articular / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D024043:Collagen Type II / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D066298:In Vitro Techniques; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D053674:Aggrecans; D024043:Collagen Type II; C497250:Ddit3 protein, mouse; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D053509:Matrix Metalloproteinase 13
keywords: C/EBP homologous protein; Cartilage degeneration; Chondrocyte apoptosis; Endoplasmic reticulum stress