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Objective. Protein kinase-like endoplasmic reticulum kinase (PERK) and protein kinase R (PKR) have been implicated in pro-inflammatory cytokine-mediated cartilage degradation in vitro and endoplasmic reticulum stress-induced arthritis, respectively. This lecture will cover the background to this project and then describe our recent study aimed to establish whether knockout of the cellular inhibitor of PERK and PKR, P58IPK results in a degenerative joint phenotype in vivo.
Materials & 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 joints scored using the OARSI system for degenerative changes. Bone changes were assessed by radiology and high-resolution micro-computed tomography of hind limbs. Phosphorylated PERK was immunolocalised in joint sections.
Results. Knockout mice exhibited narrower tibiae and smaller epiphyses in tibiae and femora. Older knockout mice had reduced total volume inside the periosteal envelope of the femora, reduced tibial and femoral bone volumes and reduced femoral bone volume fraction. OARSI scores were increased in medial femoral condyles of 12-13 month old P58IPK null mice but decreased in the lateral tibial plateau of null mice. A subset of null mice displayed severe joint degeneration with complete loss of the articular cartilage from the medial compartment and heterotopic chondro-osseous tissue formation in the medial joint capsule. These animals exhibited active PERK throughout the knee joint.
Conclusion. This study reveals a critical role for P58IPK in maintaining joint integrity, implicating PKR, PERK and endoplasmic reticulum stress in bony changes underlying the pathogenesis of joint degeneration in vivo.
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