The balance of phosphate handling is now realized to occur through endocrine communication between the skeleton and kidneys. Low serum phosphate leads to severe growth plate defects, whereas elevated serum phosphate results in ectopic calcification of the vasculature and soft tissues. Mendelian disorders and their orthologous mouse models involving defects of growth plate formation and of calcinosis have brought to light new and important information regarding bone formation and mineral ion handling. Recent work examining the molecular mechanisms causing heterogeneous diseases of mineral metabolism involving the loss of function in both FGF23 and genes that control the pyrophosphate/inorganic phosphate, such as ENPP1, has led to the possibility of layers of local communication within the bone and kidney endocrine axes. Loss of function mutations in FGF23 combined with genomic analyses identifying SNPs in modifier genes may reveal complex systemic interactions that dictate the severity of calcification phenotypes. Certainly, the combined undertaking of clinical, basic, and translational research approaches has produced the largest impact on determining the molecular events dictating extracellular phosphate and effects on bone structure and function. The events regulating the intracellular processing of hormones such as FGF23 in the context of testing direct glycosylation and phosphorylation, as well as the regulated cleavage and inactivation of this hormone, may reveal new control points in bone metabolism for therapeutic interventions in both rare disorders as well as in common diseases such as CKD. Finally, emerging therapies directly targeting defects in mineral metabolism may offer alternatives to standard therapies that only address downstream disease manifestations.
Disclosure: Receipt of grants/research support: Eli Lilly; Royalties: Kyowa Hakko Kirin.
27 - 30 Jun 2015