Basic calcium phosphate crystals: pathways to joint degeneration

PURPOSE OF REVIEWBasic calcium phosphate crystals have long been associated with rheumatic syndromes. Although an understanding of the molecular mechanisms involved in generating these pathological effects has been significantly advanced in recent years, it is still incomplete. RECENT FINDINGSBasic calcium phosphate crystals have been shown to increase prostaglandin E2 production in human fibroblasts, mediated by the induction of both cyclooxygenases 1 and 2. Basic calcium phosphate crystals have also been found to upregulate IL-1β in fibroblasts and chondrocytes. The upregulation of inducible nitric oxide synthase and stimulation of nitric oxide production in chondrocytes by octacalcium phosphate crystals has been demonstrated. The involvement of protein kinase C isoforms in basic calcium phosphate crystal-mediated matrix metalloproteinase 1 and 3 expression in human fibroblasts has been clarified. Two pathways are involvedprotein kinase Cα mediates the calcium-dependent pathway, whereas protein kinase Cμ activates the extracellular-regulated kinase pathway in a calcium-independent cascade. In addition, basic calcium phosphate crystals activate the transcription factor Egr-1, an effect that may contribute to the mitogenic effect of these crystals on fibroblasts. SUMMARYRecent findings have emphasized the potential for basic calcium phosphate crystals to stimulate the production of a variety of inflammatory mediators such as prostaglandin E2, nitric oxide, IL-1β and matrix metalloproteinases, and have helped to elucidate the mechanisms of these effects. Such advances are essential for the ongoing search for effective therapies for basic calcium phosphate crystal-associated diseases.