Cellular Responses to Inorganic Phosphate in Physiological and Pathological Processes

Phosphate is an essential chemical component of all known living organisms and is present in a variety of biological molecules such as nucleic acids and phospholipids. In vertebrates, phosphate is one of the primary ionic constituents of bone mineral. Phosphate homeostasis is maintained by a balance of absorption in the intestine, storage in pools such as bone and soft tissue, and excretion in the kidney. The flow of phosphate through these sites is controlled by several interacting hormone systems, including parathyroid hormone, vitamin D and the recently discovered endocrine hormone fibroblast growth factor 23. Loss of appropriate control of phosphate homeostasis can result in structural defects in bone if phosphate supply is inadequate, or can lead to mineralization of soft tissues if phosphate is present in excess. In human diseases or animal models characterized by impaired function of fibroblast growth factor 23 or its co-receptor Klotho, phosphate is not sufficiently eliminated by the kidney and excess phosphate accumulates. This results in ectopic mineralization in soft tissues and a variety of other pathological consequences, ultimately increasing risk of death. Previous research in the areas of osteoblast development and pathological mineralization in vascular tissue has indicated that excess extracellular phosphate causes changes in cellular behavior. We performed a series of experiments to examine in detail what effects excessive extracellular phosphate might have both on individual cells and on the organism as a whole. We found that treatment with elevated extracellular phosphate caused acute activation of cellular signaling pathways and induced expression of the mineral binding protein osteopontin in osteoblasts and fibroblasts. We found evidence that these responses are likely not the result of interaction of cells with phosphate per se but with calcium phosphate precipitates that form in the experimental conditions used. We found that diets containing higher than normal phosphate had adverse effects on mice, such as weight loss and kidney fibrosis. There is accumulating clinical evidence that such insoluble calcium phosphate particles arise in conditions of phosphate excess such as chronic kidney disease. Greater understanding of the formation and clearance of such particles may aid in the management of pathologies caused by phosphate excess.