Animal models have been developed to explore the roles of cytokines in OA pathogen-esis , (see Chapter 9), and recent studies have examined OA susceptibility in transgenic or knockout mouse models with disrupted cytokine expression or signaling (Table 3.1). In the STR/ort mouse that develops spontaneous OA, the catabolic cytokines are expressed in association with lesions . In a number of animal models, delivery of an IL-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1, to affected joints by injection or gene transfer, ex vivo or in vivo, inhibits chondrocyte catabolism and cartilage degeneration (for review see [52,58,67,167,223]. In surgically induced models of OA, ex vivo or in vivo gene therapy for an adenoviral vector encoding IL-1Ra resulted in significant inhibition of cartilage degradation [62,245]. Paradoxically, gene deletion of IL-1^ or IL-1^-converting enzyme (ICE) seems to accelerate the development of surgically induced knee OA in mice after tran-section of the medial collateral ligament and partial medial meniscectomy . Clements et al  suggested that IL-1^ may be essential for maintenance of healthy cartilage, and that overcompensation by other genes with similar activities, such as TNF-a or IL-1a, may increase susceptibility to cartilage degradation. Alternatively, these authors raised the question of whether differential vulnerability of the contralateral joint, which served as an unoperated control, could enhance the spontaneous arthritis . However, Glasson and colleagues [65,66] have shown that IL-1 knockout mice are protected against surgically induced OA. In addition, a study in two murine models of OA has shown that Pral-nacasan, an ICE inhibitor, which would also inhibit IL-18 activation, reduces joint damage significantly . In chronic arthritis models, IL-1 knockout mice are protected against cartilage erosion. Moreover, because removal of macrophages from the synovial lining ameliorates OA pathology, synovial inflammation seems to be an important component . No published report is available to date concerning efficacy of a TNF-a inhibitor in an animal model of OA.
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