title: Loss of Vhl in cartilage accelerated the progression of age-associated and surgically induced murine osteoarthritis.
abstract: OBJECTIVE
  To investigate the role of Vhl in maintaining the integrity of articular cartilage and in the development of experimental osteoarthritis (OA).
  
  
  METHODS
  Histology of articular cartilage and subchondral bone in both Vhl cKO and WT mice were analyzed by histopathology and micro-CT. Articular cartilage destruction and proteoglycan loss were scored in aged (12-month-old) mice as well as in mice with surgically induced OA. Apoptosis of cartilage in age-related and surgically induced OA was detected with TUNEL assay. Expressions of von Hippel-Lindau (VHL), Fas, LC-3, HIF-1α, HIF-2α, p-mTOR and MMP-13 in the knee joints were analyzed by immunostaining.
  
  
  RESULTS
  No gross differences in cartilage were observed between Vhl cKO and WT mice at age 4 months. However, Vhl cKO mice displayed accelerated age-associated spontaneous OA and surgically induced OA. Cartilage destruction and proteoglycan loss were observed in the absence of Vhl. In addition, inactivation of Vhl resulted in up-regulation of HIF-2α and increased chondrocyte apoptosis and decreased expression of autophagy during OA development. Immunohistochemical staining also showed that Vhl deficiency led to increased expression of Fas, p-mTOR and MMP-13, and those genes were associated with cell apoptosis, autophagy and cartilage matrix breakdown, respectively.
  
  
  CONCLUSIONS
  Loss of Vhl in adult articular cartilage is associated with earlier dysregulation of cartilage homeostasis, characterized by an increased chondrocyte apoptosis, compromised chondrocyte autophagy, and an accelerated age-related and surgery-induced OA development. These results highlight the novel role of Vhl in maintaining joint homeostasis and OA development.
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: T
authors.initials: T
authors.lastname: Weng
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: L
authors.initials: L
authors.lastname: Yi
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: F
authors.initials: F
authors.lastname: Luo
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Orthopedics, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Rheumatic Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China. Electronic address: linchen70@163.com.
authors.forename: L
authors.initials: L
authors.lastname: Chen
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D019902:Chondrocytes; D018450:Disease Progression; D007719:Knee Joint / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C494469:VHL protein, mouse
keywords: Apoptosis; Autophagy; Hypoxia-inducible factor α (HIFα); Osteoarthritis; von Hippel–Lindau gene (Vhl)