title: Deletion of P58(IPK), the Cellular Inhibitor of the Protein Kinases PKR and PERK, Causes Bone Changes and Joint Degeneration in Mice.
abstract: OBJECTIVE
  Protein kinase-like endoplasmic reticulum kinase (PERK) and protein kinase R (PKR) are implicated in endoplasmic reticulum stress-induced arthritis and pro-inflammatory cytokine-mediated cartilage degradation in vitro, respectively. We determined whether knockout of the cellular inhibitor of PERK and PKR, P58(IPK) causes joint degeneration in vivo and whether these molecules are activated in human osteoarthritis (OA).
  
  
  METHODS
  Sections of knee joints from P58(IPK)-null and wild-type mice aged 12-13 and 23-25 months were stained with toluidine blue and scored for degeneration using the osteoarthritis research society international (OARSI) system. Bone changes were assessed by radiology and high-resolution micro-computed tomography of hind limbs. Sections from the medial tibial plateaus of two human knees, removed in total knee replacement surgery for OA, were immunolabelled for phosphorylated PERK and PKR and P58(IPK).
  
  
  RESULTS
  Knockout mice exhibited narrower tibiae (p = 0.0031) and smaller epiphyses in tibiae (p = 0.0004) and femora (p = 0.0214). Older knockout mice had reduced total volume inside the femoral periosteal envelope (p = 0.023), reduced tibial (p = 0.03), and femoral (p = 0.0012) bone volumes (BV) and reduced femoral BV fraction (p = 0.025). Compared with wild-types, younger P58(IPK)-null mice had increased OARSI scores in medial femoral condyles (p = 0.035). Thirty four percent of null mice displayed severe joint degeneration with complete articular cartilage loss from the medial compartment and heterotopic chondro-osseous tissue in the medial joint capsule. Phosphorylated PERK and PKR were localized throughout human osteoarthritic tibial plateaus but, in particular, in areas exhibiting the most degeneration. There was limited expression of P58(IPK).
  
  
  CONCLUSIONS
  This study is the first to reveal a critical role for P58(IPK) in maintaining joint integrity in vivo, implicating the PKR and PERK stress signaling pathways in bony changes underlying the pathogenesis of joint degeneration.
authors.affiliation: Pathophysiology and Repair Division, Arthritis Research UK Biomechanics and Bioengineering Centre, School of Biosciences, Cardiff University , Cardiff , UK.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Gilbert
authors.affiliation: School of Veterinary Sciences, University of Bristol , Bristol , UK.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Meakin
authors.affiliation: Pathophysiology and Repair Division, Arthritis Research UK Biomechanics and Bioengineering Centre, School of Biosciences, Cardiff University , Cardiff , UK.
authors.forename: Cleo S
authors.initials: CS
authors.lastname: Bonnet
authors.affiliation: Section of Inflammation, Skin and Joint Disease, Institute of Infection and Immunity, School of Medicine, Cardiff University , Cardiff , UK.
authors.forename: Mari A
authors.initials: MA
authors.lastname: Nowell
authors.affiliation: Department of Comparative Medicine, School of Medicine, University of Washington , Seattle, WA , USA.
authors.forename: Warren C
authors.initials: WC
authors.lastname: Ladiges
authors.affiliation: Department of Comparative Medicine, School of Medicine, University of Washington , Seattle, WA , USA.
authors.forename: John
authors.initials: J
authors.lastname: Morton
authors.affiliation: Pathophysiology and Repair Division, Arthritis Research UK Biomechanics and Bioengineering Centre, School of Biosciences, Cardiff University , Cardiff , UK.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Duance
authors.affiliation: Pathophysiology and Repair Division, Arthritis Research UK Biomechanics and Bioengineering Centre, School of Biosciences, Cardiff University , Cardiff , UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Mason
keywords: P58IPK; PERK; PKR; articular cartilage; bone; osteoarthritis