The Genetics and Outcomes of an Altered FGF23-1,25D-PTH Axis in Diseases of Mineral Metabolism.

Abstract

The molecular mechanisms causing heritable disorders of hypo- and hyperphosphatemia involving the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) and its co-receptor αKlotho (KL) have sprung new concepts underlying the endocrine control of phosphate and calcium (Ca), as well as the regulation of the active form of vitamin D, 1α,25-dihydroxy vitamin D3 (1,25D). These critical developments have proven important for the understanding and treatment of both rare, Mendelian diseases as well as for important implications for common disorders of blood phosphate excess and dysregulated 1,25D metabolism such as chronic kidney disease (CKD). The heritable and acquired diseases associated with FGF23 are caused by changes in the levels and proteolytic control of this hormone, revealing novel mechanisms dictating FGF23 synthesis and systemic mineral metabolism. Further, new interactions between FGF23, 1,25D, and parathyroid hormone (PTH) on phosphate, Ca, and 1,25D at the molecular and genomic level are emerging particularly in the bone-kidney axis. These disorders will be reviewed herein, including considerations for genetic analyses and therapeutic strategies, recently discovered regulation of critically intertwined signaling that controls endocrine-mediated bone and mineral metabolism, as well as gaps in our current knowledge.