title: Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis.
abstract: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation.
  
  
  
  Knee joints of WT and Phlpp1(-/-) mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines.
  
  
  
  Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1(-/-) mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines.
  
  
  
  Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Bradley
authors.affiliation: Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Carpio
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: McGee-Lawrence
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: C
authors.initials: C
authors.lastname: Castillejo Becerra
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Amanatullah
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Ta
authors.affiliation: Research Division, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: M
authors.initials: M
authors.lastname: Otero
authors.affiliation: Research Division, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Goldring
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kakar
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: westendorf.jennifer@gmail.com.
authors.forename: J J
authors.initials: JJ
authors.lastname: Westendorf
mesh_terms: D000818:Animals; D002358:Cartilage, Articular; D019902:Chondrocytes; D000073398:Demethylation; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D051379:Mice; D009687:Nuclear Proteins; D010003:Osteoarthritis / Q000209:etiology*; D010749:Phosphoprotein Phosphatases
chemical_list: D009687:Nuclear Proteins; C400601:PHLPP1 protein, human; C519282:PHLPP1 protein, mouse; D010749:Phosphoprotein Phosphatases
keywords: Articular cartilage; DMM mouse model; DNA methylation; Il6; Mechanical allodynia; TNFα