NSAID STIMULATION OF HUMAN CARTILAGE MATRIX SYNTHESIS - A STUDY OF THE MECHANISM OF ACTION OF ACECLOFENAC

In terms of their effects on matrix synthesis by the indigenous chondr ocytes of human articular cartilage, it has been suggested that NSAIDs fall into three categories: those exemplified by aceclofenac and teni dap that are capable of stimulating matrix synthesis, whilst others, w hich include piroxicam, aspirin and nabumetone, do not appear to have a major effect on matrix synthesis, and a third group, which includes ibuprofen, indomethacin, nimesulide and naproxen, that are markedly in hibitory in terms of matrix synthesis. Whilst the inhibitory effect of certain NSAIDs can be ascribed to toxic effects of the compounds or t heir metabolites, it has been difficult to understand the mechanism wh ereby some NSAIDs could stimulate matrix synthetic activity. This pape r demonstrates the sensitivity of human cartilage synthetic activity t o inhibition by the cytokine interleukin (IL)-1 and confirms that glyc osaminoglycan synthesis is responsive to growth factors such as insuli n-like growth factor (IGF)-1. The present work showed that the stimula tory effect of NSAIDs does not take place in the absence of serum. The serum, however, may be replaced by IGF-1 at 100 mu g/L. In the presen ce of this growth factor, the inhibition by IL-1 may be partially reve rsed in the presence of aceclofenac. The recovery from an episode of I L-1 is also increased in the presence of aceclofenac. These experiment s lead to the hypothesis that the stimulatory actin of NSAIDs is due t o the inhibition of locally produced IL-1 and the consequent expressio n of growth factor activity. Other NSAIDs that may also inhibit IL-1 s ynthesis or release probably do not have a marked effect as they have toxic effects on cartilage metabolism. The dose curve of tenidap is pr obably an expression of the balance between stimulation at low concent rations (by allowing growth factor activity to function), and inhibiti on due to toxic effect at higher concentrations. Aceclofenac does not appear to be toxic at the highest plasma concentrations, although ther e is a peak of activity around 2 mg/L. These experiments lead to the s uggestion that NSAIDs such as aceclofenac would be appropriate for the long-term treatment of arthritic conditions provided that one is prep ared to extrapolate between in vitro experiments on human cartilage an d what may be happening in vivo.