Chondroprotection, myth or reality: An experimental approach

Abstract

A CHARACTERISTIC feature of osteoarthritis (OA) and chronic rheumatoid arthritis (RA) is the progressive decline in the structural integrity of joint articular cartilage. The ability of a therapeutic substance to prevent this process has led to the concept of chondroprotection but the manner by which chondroprotection can be achieved in practise has not been adequately defined. The mechanisms responsible for failure of cartilage in osteoarthritic joints are still the subject of debate, particularly with regard to whether the primary lesion occurs within cartilage-a chondrocyte/matrix defect, in the subchondral bone-a decrease in compliance, or in the synovium-production of inflammatory mediators and/or proteinases. Irrespective of the initiating event, it is clear that once joint dysfunction is established all these tissues (cartilage, synovial fluid, synovium and subchondral bone) can contribute to progression of the disorder. The situation is summarised in Figure 1, and on these grounds, therapeutic intervention in OA should not be exclusively directed to articular cartilage but must also address the synovial inflammation”* and inadequacies which exist in the synovial fluid3 and subchondral blood s~pply.‘*~ Today, steroidal and nonsteroidal antiinflammatory drugs (NSAIDs) represent the mainstay of nonsurgical treatment of the arthritic patient. Evidence is accumulating to suggest that some of these agents may provide chondroprotection by attenuating the release from activated synovial cells of cytokines, oxygen derived free radicals, and proteinases that are capable of directly or indirectly degrading components of the cartilage matrix.‘-’ However, the effects that NSAIDs may have on the biosynthesis of hyaluronic acid (HA) by synovial fibroblasts has not been previously investigated. Recent studies’,’ with prednisone and triamcinolone hexacetonide have suggested that corticosteroids may provide a chondroprotective effect in OA, since in animal models cartilage lesions and osteophytes were reduced. Corticosteroids act by down regulating cell metabolism” and although this mode of action may be beneficial in the shortterm, by suppressing cell proliferation and the synthesis of proteinases and inflammatory mediators, the long-term consequences, particularly in relation to the inhibition of proteoglycan and HA synthesis by chondrocytes and synovial cells, has limited their application.” Polysulphated polysaccharides, such as glycosaminoglycan polysulphate ester (Arteparon@) and pentosan polysulphate (Cartrophen@) have been demonstrated to exhibit a chondroprotective effect in a variety of in vitro and in vivo systems ‘*‘l-13. however, the action of this class of drugs on synoviocyte proliferation and biosynthesis of HA has received only limited attention. In the present study, the effects of pentosan polysulphate (PPS) and three NSAIDs (tiaprofenic acid, diclofenac sodium, and piroxicam) on DNA and HA biosynthesis, by synovial fibroblast cultures obtained from OA and RA knee joints, were investigated.