NSAID Stimulation of Human Cartilage Matrix Synthesis

Abstract

In terms of their effects on matrix synthesis by the indigenous chondrocytes of human articular cartilage, it has been suggested that NSAIDs fall into three categories: those exemplified by aceclofenac and tenidap that are capable of stimulating matrix synthesis, whilst others, which 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 inhibitory in terms of matrix synthesis. Whilst the inhibitory effect of certain NSAIDs can be ascribed to toxic effects of the compounds or their metabolites, it has been difficult to understand the mechanism whereby some NSAIDs could stimulate matrix synthetic activity. This paper demonstrates the sensitivity of human cartilage synthetic activity to inhibition by the cytokine interleukin (IL)-1 and confirms that glycosaminoglycan synthesis is responsive to growth factors such as insulin-like growth factor (IGF)-1. The present work showed that the stimulatory effect of NSAIDs does not take place in the absence of serum. The serum, however, may be replaced by IGF-1 at 100 µg/L. In the presence of this growth factor, the inhibition by IL-1 may be partially reversed in the presence of aceclofenac. The recovery from an episode of IL-1 is also increased in the presence of aceclofenac. These experiments lead to the hypothesis that the stimulatory action of NSAIDs is due to the inhibition of locally produced IL-1 and the consequent expression of growth factor activity. Other NSAIDs that may also inhibit IL-1 synthesis or release probably do not have a marked effect as they have toxic effects on cartilage metabolism. The dose curve of tenidap is probably an expression of the balance between stimulation at low concentrations (by allowing growth factor activity to function), and inhibition due to toxic effects at higher concentrations. Aceclofenac does not appear to be toxic at the highest plasma concentrations, although there is a peak of activity around 2 mg/L. These experiments lead to the suggestion that NSAIDs such as aceclofenac would be appropriate for the long-term treatment of arthritic conditions provided that one is prepared to extrapolate between in vitro experiments on human cartilage and what may be happening in vivo.