Coupling between phosphate and calcium homeostasis: a mathematical model

Abstract

We developed a mathematical model of calcium (Ca) and phosphate (PO4) homeostasis in the rat to elucidate the hormonal mechanisms that underlie the regulation of Ca and PO4balance. The model represents the exchanges of Ca and PO4between the intestine, plasma, kidneys, bone, and the intracellular compartment, and the formation of Ca-PO4-fetuin-A complexes. It accounts for the regulation of these fluxes by parathyroid hormone (PTH), vitamin D3, fibroblast growth factor 23, and Ca2+-sensing receptors. Our results suggest that the Ca and PO4homeostatic systems are robust enough to handle small perturbations in the production rate of either PTH or vitamin D3. The model predicts that large perturbations in PTH or vitamin D3synthesis have a greater impact on the plasma concentration of Ca2+([Ca2+]p) than on that of PO4([PO4]p); due to negative feedback loops, [PO4]pdoes not consistently increase when the production rate of PTH or vitamin D3is decreased. Our results also suggest that, following a large PO4infusion, the rapidly exchangeable pool in bone acts as a fast, transient storage PO4compartment (on the order of minutes), whereas the intracellular pool is able to store greater amounts of PO4over several hours. Moreover, a large PO4infusion rapidly lowers [Ca2+]powing to the formation of CaPO4complexes. A large Ca infusion, however, has a small impact on [PO4]p, since a significant fraction of Ca binds to albumin. This mathematical model is the first to include all major regulatory factors of Ca and PO4homeostasis.