Cytokine targeting in osteoarthritis.

Cytokines are involved in osteoarthritis (OA) at several levels. They are involved in primary cartilage damage, but also in synovial activation that is observed in osteoarthritic joints. From in vitro studies and animal models for OA, several cytokines have been identified that are potential targets for OA therapy. Two promising targets are the destructive cytokine Interleukin-1 (IL-1) and the anabolic growth factor transforming growth factor (TGF)beta and these will be discussed in more detail. Inhibition of IL-1 has been proven to result in amelioration of osteoarthritis-like pathology in animal models and the role of IL-1 is substantiated in studies in IL-1 deficient mice. In contrast, application of the anabolic growth factor TGFbeta may provide an alternative approach to promote cartilage integrity and repair. TGFbeta is a potent stimulator of chondrocyte matrix production, and therefore has a potency to repair already damaged cartilage. However, TGFbeta induces tissue fibrosis and osteophytes at the joint margins and can only be applied to promote cartilage repair when these side effects can be blocked. This appears possible with concomitant, compartmentalized application of selective inhibitors of TGFbeta in soft tissues, using local gene therapy with inhibitory Smad 6 and 7. Since OA is often limited to a few joints, local gene therapy may provide a suitable way to treat OA patients. Depending on the phenotype of a particular OA patient, e.g. with or without marked synovial activation, treatment may be focused mainly on suppression of catabolism or stimulation of anabolism, but combination therapy seems most warranted.