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, P58IPK causes joint degeneration in vivo and whether these molecules are activated in human osteoarthritis (OA).Materials and Methods: Sections of knee joints from P58IPK-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 P58IPK.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 P58IPK-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 P58IPK.Conclusion: This study is the first to reveal a critical role for P58IPK in maintaining joint integrity in vivo, implicating the PKR and PERK stress signaling pathways in bony changes underlying the pathogenesis of joint degeneration.
Highlights
Osteoarthritis (OA) is a disease of the synovial joint associated with pathological changes in the bone and cartilage that cause pain and disability
Phosphorylated protein kinase-like endoplasmic reticulum kinase (PERK) and protein kinase R (PKR) were localized throughout human osteoarthritic tibial plateaus but, in particular, in areas exhibiting the most degeneration
This study is the first to reveal a critical role for 58 kDa inhibitor protein kinase (P58IPK) in maintaining joint integrity in vivo, implicating the PKR and PERK stress signaling pathways in bony changes underlying the pathogenesis of joint degeneration
Summary
Osteoarthritis (OA) is a disease of the synovial joint associated with pathological changes in the bone and cartilage that cause pain and disability. Several studies have implicated the stress-activated protein kinase R (PKR) and protein kinase-like endoplasmic reticulum kinase (PERK) signaling pathways in the pathogenesis of arthritic disease [3,4,5,6,7,8,9]. PKR is constitutively expressed in all cells, with levels increasing upon cellular stress [reviewed in Ref. Constitutive PKR expression is known to be high [8], with further activation (phosphorylation) resulting from cellular stress leading to up-regulation of matrix degrading enzymes [3, 8], proteoglycan degradation [3, 4], phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) [11] and down-regulation of protein synthesis [reviewed in Ref. The PKR pathway is mechano-responsive, gene expression being up-regulated [12]
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