Role of phosphate sensing in bone and mineral metabolism

Inorganic phosphate (P-i) is essential for signal transduction and cell metabolism, and is also an essential structural component of the extracellular matrix of the skeleton. P-i is sensed in bacteria and yeast at the plasma membrane, which activates intracellular signal transduction to control the expression of P-i transporters and other genes that control intracellular P-i levels. In multicellular organisms, P-i homeostasis must be maintained in the organism and at the cellular level, requiring an endocrine and metabolic P-i-sensing mechanism, about which little is currently known. This Review will discuss the metabolic effects of P-i, which are mediated by P-i transporters, inositol pyrophosphates and SYG1-Pho81-XPR1 (SPX)-domain proteins to maintain cellular phosphate homeostasis in the musculoskeletal system. In addition, we will discuss how P-i is sensed by the human body to regulate the production of fibroblast growth factor 23 (FGF23), parathyroid hormone and calcitriol to maintain serum levels of P-i in a narrow range. New findings on the crosstalk between iron and P-i homeostasis in the regulation of FGF23 expression will also be outlined. Mutations in components of these metabolic and endocrine phosphate sensors result in genetic disorders of phosphate homeostasis, cardiomyopathy and familial basal ganglial calcifications, highlighting the importance of this newly emerging area of research.