Basic Calcium Phosphate Crystals: Pathways to Joint Degeneration
Basic Calcium Phosphate Crystals: Pathways to Joint Degeneration
Purpose of Review: Basic 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 Findings: Basic 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 involved: protein 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.
Summary: Recent 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.
Basic calcium phosphate (BCP) crystals are predominantly composed of partly carbonate-substituted hydroxyapatite, but also include octacalcium phosphate, tricalcium phosphate and magnesium whitlockite. BCP crystals are associated with a number of rheumatic syndromes, including acute calcific periarthritis, soft tissue calcification, osteoarthritis and other degenerative arthropathies such as Milwaukee shoulder syndrome (MSS). They have also recently been linked to breast cancer and atherosclerosis.
The key mechanisms whereby BCP crystals may cause tissue damage are: (1) the induction of mitogenesis; (2) the upregulation of matrix metalloproteinase (MMP) production; (3) the stimulation of cyclooxygenases 1 and 2 and prostaglandin E2 production; (4) the stimulation of cytokine production, in particular IL-1β; and (5) the induction of nitric oxide (NO) production. This paper reviews recent work that has advanced the understanding of the mechanisms contributing to the pathogenesis of the rheumatic syndromes associated with BCP crystal deposition.
Abstract and Introduction
Abstract
Purpose of Review: Basic 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 Findings: Basic 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 involved: protein 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.
Summary: Recent 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.
Introduction
Basic calcium phosphate (BCP) crystals are predominantly composed of partly carbonate-substituted hydroxyapatite, but also include octacalcium phosphate, tricalcium phosphate and magnesium whitlockite. BCP crystals are associated with a number of rheumatic syndromes, including acute calcific periarthritis, soft tissue calcification, osteoarthritis and other degenerative arthropathies such as Milwaukee shoulder syndrome (MSS). They have also recently been linked to breast cancer and atherosclerosis.
The key mechanisms whereby BCP crystals may cause tissue damage are: (1) the induction of mitogenesis; (2) the upregulation of matrix metalloproteinase (MMP) production; (3) the stimulation of cyclooxygenases 1 and 2 and prostaglandin E2 production; (4) the stimulation of cytokine production, in particular IL-1β; and (5) the induction of nitric oxide (NO) production. This paper reviews recent work that has advanced the understanding of the mechanisms contributing to the pathogenesis of the rheumatic syndromes associated with BCP crystal deposition.
