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Knockout of P58(IPK), a known inhibitor of PKR, in mice results in a degenerative phenotype in the knee joint

Gilbert, Sophie Jane, Patel, M., Toumi, H., Duance, Victor Colin and Mason, Deborah Jane 2010. Knockout of P58(IPK), a known inhibitor of PKR, in mice results in a degenerative phenotype in the knee joint. International Journal of Experimental Pathology 91 (2) , A34-A34. 10.1111/j.1365-2613.2009.00690.x

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Abstract

Introduction Our work has implicated the TNF-activated protein kinase, PKR in cartilage degradation (Gilbert et al. 2004). PKR mediates various signal transduction pathways regulating apoptosis, cell proliferation and pro-inflammatory responses, all of which are important in the pathology of arthritic diseases. Our in vitro studies support a role for PKR in arthritis since TNF-alpha-induced degradation of cartilage is prevented by PKR inhibition. Here we report that absence of P58IPK, an inhibitor of PKR, in mice (Ladiges et al. 2005) is associated with a degenerative joint phenotype. Materials and Methods Degenerative changes were measured in the knees of male P58IPK)/) mice and wild-type littermates at 12, 18 and 24 months (2 wild-type and 2 P58IPK)/) at each age). Coronal, decalcified sections were taken from several points throughout the knee joint and scored for degenerative changes using our modified Mankin score. Tibial cancellous bone volume was quantified using image analysis software (Toumi et al. 2006) to assess degenerative changes of the bone. Results P58IPK)/) mice developed significantly more severe cartilage damage than wild-type littermates. The total Mankin score in the knockout mice ranged from 55 to 91 (68.3 ± 16.10, n = 6), and in the wild-type mice it ranged from 24 to 44 (32.4 ± 7.96, n = 6). One-way ANOVA indicated that the difference between the two groups of mice was significant (P = 0.002). The difference in Mankin score between the two groups increased with age, indicating accelerated progression of cartilage degeneration in the knockout mice. Bone volume analysis did not show signifi- cant differences between the two groups but the mean bone volume in the knockouts was lower than in wild type mice (68.7% vs. 71%). Bone volume in knockout mice decreased by 4.5% as the mice aged from 12 months to 24 months, whereas in wild type mice, bone volume remained fairly constant. Discussion This study shows that P58IPK)/) mice develop significantly more severe cartilage damage than wild-type littermates, and that this difference increased with age, indicating accelerated progression of cartilage degeneration. These findings support our recent studies implicating PKR in arthritis and provide a new animal model for further studies on the pathological mechanisms of arthritic disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QR Microbiology
Publisher: Wiley-Blackwell
ISSN: 0959-9673
Last Modified: 02 May 2019 11:05
URI: http://orca.cf.ac.uk/id/eprint/69048

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