Calcium and disease: molecular determinants of calcium crystal deposition diseases.
Deposition of basic calcium phosphate (hydroxyapatite, octacalcium phosphate and tricalcium phosphate) (BCP) and crystalline calcium pyrophosphate dihydrate (CPPD) is associated with a variety of aging-related pathologies, including osteoarthritis, cartilage degeneration and pseudogout. These diseases of calcium deposition serve as some of the best-studied examples of how calcium-regulated changes in gene expression can directly lead to pathogenic consequences. Tissue damage can result when crystals stimulate cells to release matrix-degrading molecules or secrete cytokines that stimulate the release of matrix-degrading molecules. Exposure of cultured cells to crystals induces expression of cellular proto-oncogenes such as c-fos, c-myc and c-jun, by a calcium-dependent mechanism, and this response can be blocked by a potential therapeutic compound, phosphocitrate. Activation of the c-fos and c-jun genes is directly involved in expression of metalloproteinases such as collagenase and stromelysin, suggesting that crystal-mediated activation of these genes is directly involved in pathogenesis. In this review recent advances in the molecular mechanisms responsible for crystal-mediated cell activation are discussed.
Misra
R P
RP
Department of Biochemistry, Medical College of Wisconsin, Milwaukee 53226, USA. rmisra@mcw.edu
D000818:Animals; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015398:Signal Transduction
D002118:Calcium