Bone Abstracts

Objective: The protein kinases, PKR, and PERK have been implicated in pro-inflammatory cytokine-mediated cartilage degradation in vitro and endoplasmic reticulum stress-induced arthritis respectively. The objective of this study was to establish whether loss of P58^IPK, an inhibitor of PKR and PERK, results in a degenerative joint phenotype in vivo.

Methods: Sections of knee joints from P58^IPK-null and wild-type mice aged 12–13, 18, and 23–25 months were stained with Toluidine blue, joints scored using the OARSI system for degenerative changes and subchondral bone areas measured. In addition, bone changes were assessed by radiology of hind limbs. To determine the presence of ER stress, immunohistochemistry was carried out using antibodies to phosphorylated PERK and GADD153.

Results: P58^IPK null mice demonstrated significantly higher total OARSI scores in the medial femoral condyle (P=0.016) as well as significant remodelling of the bone (P=0.013). In addition, medial tibial plateau bone area was increased in younger (P=0.033), but significantly lower in older (P=0.02), null mice. Bone area and cartilage damage within the lateral tibial plateau of null mice were reduced. A severe phenotype was observed in a subset of null mice with complete loss of the articular cartilage from the medial compartment and heterotopic chondro-osseous tissue formation in the capsule surrounding the medial meniscus. Although, phosphorylated PERK and GADD153 were detected in both null and wild-type mice, the loss of P58^IPK resulted in more extensive staining throughout the joint.

Conclusions: This is the first demonstration of a critical role for P58^IPK in maintaining joint integrity, implicating PKR and PERK in the pathogenesis of joint degeneration in vivo. Remodelling of the medial compartment suggests that mechanical load within the joint may precipitate degenerative changes. Thus PKR/PERK may be influenced by mechanical as well as inflammatory signals important in osteoarthritis.