Novel strategies for the treatment of osteoarthritis.

Osteoarthritis is a worldwide heterogeneous group of conditions that leads to joint symptoms, which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins. The prevalence of the disease after the age of 65 years, is about 60% in men and 70% in women. The aetiology of osteoarthritis is multifactorial, with the end result being mechanical joint failure and varying degrees of loss of joint function. The pathophysiological events associated with osteoarthritis are beginning to be understood. Essential inflammatory cytokines, such as IL-1beta and TNF-alpha, are involved initiating a vicious cycle of catabolic and degradative events in cartilage, mediated by metalloproteinases, which degrade cartilage extracellular matrix. The role of inflammation in the pathophysiology and progression of early osteoarthritis is supported further by the observation that C-reactive protein levels are raised in women with early knee osteoarthritis and higher levels predict those whose disease will progress. The synovium from osteoarthritis joints stains for IL-1beta and TNF-alpha. Nitric oxide, which exerts pro-inflammatory effects, is released during inflammation. Cartilage from patients with rheumatoid arthritis and osteoarthritis spontaneously produces nitric oxide in vitro. In experimental osteoarthritis, nitric oxide induces chondrocyte apoptosis, thus contributing to cartilage degradation. Hence unregulated nitric oxide production in humans plays a part in the pathophysiology of the disease. These recent observations suggest that therapy can now be targeted at specific sites of pathophysiological pathways involved in the pathogenesis of osteoarthritis. The novel strategies under consideration for the treatment of osteoarthritis can be divided into five main areas. These are COX-2 inhibitors, nitric oxide synthesis inhibitors and anti-oxidants, chondrocyte and bone growth promoters, metalloproteinase and cytokine inhibitors and gene therapy.