title: Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis.
abstract: OBJECTIVE
  It has been suggested that the lysosomal recycling process called macro-autophagy plays a role in osteoarthritis development. We thus decided to genetically ablate the autophagy-indispensable Atg5 gene specifically in chondrocytes and analyse the development of osteoarthritis upon aging and in a post-traumatic model.
  
  
  METHODS
  Mice lacking the Atg5 gene in their chondrocytes (Atg5cKO) were generated by crossing Atg5-floxed mice with transgenic mice that expressed cre recombinase driven by the collagen type 2 promoter. Animals were analysed at the age of 2, 6 and 12 months for age-related osteoarthritis or underwent mini-open partial medial meniscectomy at 2 months of age and were analysed 1 or 2 months after surgery. We evaluated osteoarthritis using the Osteoarthritis Research Society International (OARSI) scoring on safranin-O-stained samples. Cell death was evaluated by terminal deoxy-nucleotidyl-transferase-mediated deoxy-UTP nick end labelling (TUNEL) and by immunostaining of cleaved caspases.
  
  
  RESULTS
  We observed the development of osteoarthritis in Atg5cKO mice with aging including fibrillation and loss of proteoglycans, which was particularly severe in males. The ablation of Atg5 was associated with an increased cell death as assessed by TUNEL, cleaved caspase 3 and cleaved caspase 9. Surprisingly, no difference in the development of post-traumatic osteoarthritis was observed between Atg5cKO and control mice.
  
  
  CONCLUSIONS
  Autophagy protects from age-related osteoarthritis by facilitating chondrocyte survival.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thibault
authors.initials: T
authors.lastname: Bouderlique
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karuna K
authors.initials: KK
authors.lastname: Vuppalapati
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Newton
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Orthopaedic Section, Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Barenius
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrei S
authors.initials: AS
authors.lastname: Chagin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D000070600:Tibial Meniscus Injuries
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D011509:Proteoglycans; D020169:Caspases
keywords: Chondrocytes; Knee Osteoarthritis; Osteoarthritis