List the target organs and key actions of 1,25-dihydroxyvitamin D.
6.
Discuss the regulation of phosphate metabolism by FGF23.
7.
Predict the hormone responses that would be triggered by perturbations of serum calcium and phosphate or by vitamin D deficiency, and discuss the consequences of these compensatory hormone actions.
alcium (Ca) and phosphate are essential to human life because they play important structural roles in hard tissues (i.e., bones and teeth) and important regulatory roles in metabolic and signaling pathways. In biological systems, inorganic phosphate (Pi) consists of a mixture of dihydrogen phosphate (H2PO4 −) and hydrogen phosphate (HPO4 −). The two primary sources of circulating Ca and Pi are the diet and the skeleton (
Fig. 40.1 ). Two hormones, 1,25-dihydroxyvitamin D (also called calcitriol) and parathyroid hormone (PTH), regulate intestinal absorption of Ca and Pi and release of Ca and Pi into the circulation after bone resorption. The primary processes for removal of Ca and Pi from blood are renal excretion and bone mineralization (see
Fig. 40.1 ). 1,25-Dihydroxyvitamin D and PTH regulate both processes. Other hormones and paracrine growth factors also regulate Ca and Pi homeostasis.
Crucial Roles of Calcium and Phosphate in Cellular Physiology
Ca is an essential dietary element. In addition to obtaining Ca from the diet, humans contain a vast store (i.e., >1 kg) of Ca in bone mineral, which can be called upon to maintain normal circulating levels of Ca in times of dietary restriction and during the increased demands of pregnancy and nursing. Circulating Ca exists in three forms (
Table 40.1): free ionized Ca++ , protein-bound Ca, and Ca complexed with anions (e.g., phosphates, HCO3 − , citrate). The ionized form represents about 50% of circulating Ca. Since it is critical to so many cellular functions, [Ca++] in both the extracellular and intracellular compartments is tightly controlled. Circulating Ca++ is under direct hormonal control and normally maintained within a relatively narrow range. Either too little calcium (hypocalcemia; total serum calcium < 8.7 mg/dL [2.2 mM]) or too much Ca (hypercalcemia; total serum Ca > 10.4 mg/dL [2.6 mM]) in blood can lead to a broad range of pathophysiological changes, including neuromuscular dysfunction, central nervous system dysfunction, renal insufficiency, calcification of soft tissue, and skeletal pathology.
Pi is also an essential dietary element, and it is stored in large quantities in mineral. Most circulating Pi is in the free ionized form, but some Pi (<20%) circulates as a protein-bound form or complexed with cations (see
Table 40.1 ). Because soft tissues contain 10-fold more Pi than Ca, tissue damage (e.g., crush injury with massive muscle cell death) can result in hyperphosphatemia, whereupon the increased Pi complexes with Ca++ to cause acute hypocalcemia.
Pi is a key intracellular component. Indeed, it forms the high-energy phosphate bonds of adenosine triphosphate (ATP) that maintain life. Phosphorylation and dephosphorylation of proteins, lipids, second messengers, and cofactors represent key regulatory steps in numerous metabolic and signaling pathways, and phosphate also serves as the backbone for nucleic acids.
•Fig. 40.1 DailyCa++ andPiflux.
Ca8.5–10.250%45%5%Pi3–4.584%10%6%