title: Upregulation of Atrogin-1/FBXO32 is not necessary for cartilage destruction in mouse models of osteoarthritis.
abstract: In a preliminary study, we found that recently identified catabolic regulators of osteoarthritis (OA), including hypoxia-inducible factor (HIF)-2α and members of the zinc-ZIP8-MTF1 axis, upregulate the E3 ubiquitin ligase, Atrogin-1 (encoded by Fbxo32), in chondrocytes. As the ubiquitination/proteasomal degradation pathways are tightly regulated to modulate the expression of catabolic factors in chondrocytes, we examined the in vivo functions of Atrogin-1 in mouse models of OA.
  
  
  
  The mRNA and protein levels of Atrogin-1 and other regulators of OA were determined in primary cultured mouse chondrocytes, OA human cartilage, and OA cartilage from wild-type (WT) and Fbxo32-knockout (KO) mice subjected to destabilization of the medial meniscus or intra-articular (IA) injection of adenoviruses expressing HIF-2α (Ad-Epas1), ZIP8 (Ad-Zip8), or Atrogin-1 (Ad-Fbxo32). The effect of Atrogin-1 overexpression on the cartilage of WT mice was examined by IA injection of Ad-Fbxo32.
  
  
  
  Atrogin-1 mRNA levels in chondrocytes were markedly increased by treatment with interleukin-1β, HIF-2α, and members of the zinc-ZIP8-MTF1 axis. Atrogin-1 protein levels were also increased in OA cartilage from humans and various mouse OA models. However, the forced overexpression of Atrogin-1 in chondrocytes did not modulate the expression of cartilage matrix molecules or matrix-degrading enzymes. Moreover, overexpression of Atrogin-1 in the mouse joint tissues failed to cause OA pathogenesis, and Fbxo32 knockout failed to affect post-traumatic OA cartilage destruction in mice.
  
  
  
  Although Atrogin-1 is upregulated in OA cartilage, overexpression of Atrogin-1 in the joint tissues or knockout of Fbxo32 does not affect OA cartilage destruction in mice.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
authors.forename: H-E
authors.initials: HE
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Rhee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea. Electronic address: jschun@gist.ac.kr.
authors.forename: J-S
authors.initials: JS
authors.lastname: Chun
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D009124:Muscle Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases
keywords: Atrogin-1/FBXO32; Cartilage; Chondrocytes; Osteoarthritis