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Hormonal Regulation of Calcium and Phosphate Metabolism
Learning Objectives
Upon completion of this chapter the student should be able to answer the following questions:
- 1
Describe the pool of serum calcium and phosphate, including ionized, complexed, and protein bound. Describe the normal concentration ranges of these ions and the major routes of influx and efflux.
- 2
Discuss the role of the parathyroid gland in the regulation of serum calcium and explain the role of the calcium-sensing receptor in the regulation of parathyroid hormone (PTH) secretion.
- 3
Describe the production of 1,25-dihydroxyvitamin D, including sources of vitamin D precursor, sites and key regulators of vitamin D hydroxylation, and transport of vitamin D metabolites in the blood.
- 4
List the target organs of PTH and describe its effects on calcium and phosphate mobilization or handling at each of these sites.
- 5
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.
Calcium (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 (P i ) consists of a mixture of dihydrogen phosphate (H 2 PO 4 − ) and hydrogen phosphate (HPO 4 − ). The two primary sources of circulating Ca and P i 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 P i and release of Ca and P i into the circulation after bone resorption. The primary processes for removal of Ca and P i from blood are renal excretion and bone mineralization (see Fig. 40.1 ). 1,25-Dihydroxyvitamin D and PTH regulate both processes. Fibroblast Growth Factor-23 (FGF23) regulates serum P i by inhibiting its renal reabsorption.
Daily Ca ++ and P i flux.
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, HCO 3 − , 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.
TABLE 40.1
Forms of Ca and P i in Plasma
| Ion | mg/dL | Ionized | Protein Bound | Complexed |
|---|---|---|---|---|
| Ca | 8.5–10.2 | 50% | 45% | 5% |
| P i | 3–4.5 | 84% | 10% | 6% |
Ca ++ is bound (i.e., complexed) to various anions in plasma, including HCO 3 − , citrate, and SO 4 2− . P i is complexed to various cations, including Na + and K + .
From Koeppen BM, Stanton BA. Renal Physiology. 4th ed. Philadelphia: Mosby; 2007.
P i is also an essential dietary element, and it is stored in large quantities in mineral. Most circulating P i is in the free ionized form, but some P i (<20%) circulates as a protein-bound form or complexed with cations (see Table 40.1 ). Because soft tissues contain 10-fold more P i than Ca, tissue damage (e.g., crush injury with massive muscle cell death) can result in hyperphosphatemia, whereupon the increased P i complexes with Ca ++ to cause acute hypocalcemia.
P i 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.
Hormonal Regulation of Calcium and Phosphate: PTH, Vitamin D, and FGF23
Classically, PTH and 1,25-dihydroxyvitamin D are the most important hormones dedicated to the maintenance of normal blood Ca and P i in humans. As such, they are referred to as calciotropic hormones. More recently, a role for fibroblast growth factor-23 (FGF23), produced by osteocytes in bone, has been elucidated in the regulation of serum P i levels. The structure, synthesis, and secretion of these hormones and their receptors will be discussed first. In the following section, the detailed actions of PTH, 1,25-dihydroxyvitamin D, and FGF-23 on key target organs (i.e., gut, bone, and kidney) are discussed.
Parathyroid Hormone
The predominant parenchymal cell type in the parathyroid gland is the principal (also called chief ) cell ( Fig. 40.2 ). PTH produced and secreted by these cells is the primary hormone that protects against hypocalcemia. The direct targets of PTH are bone and the kidneys. PTH also functions in a positive feed-forward loop by stimulating the production of 1,25-dihydroxyvitamin D.
Structure, Synthesis, and Secretion
PTH is secreted as an 84–amino acid polypeptide and is synthesized as prepro-PTH, which is proteolytically processed to pro-PTH in the endoplasmic reticulum and then to PTH in the Golgi apparatus and secretory vesicles. PTH has a short half-life in the circulation (2 minutes), consistent with its role in minute-to-minute regulation of plasma calcium.
AT THE CELLULAR LEVEL
Extracellular [Ca ++ ] is sensed by the parathyroid chief cell through a plasma membrane calcium-sensing receptor (CaSR). The primary signal that stimulates PTH secretion is a decrease in circulating [Ca ++ ] ( Fig. 40.3 ). Conversely, increasing amounts of extracellular Ca ++ bind to the CaSR and stimulate signaling pathways that repress PTH secretion. Although the CaSR binds to extracellular Ca ++ with relatively low affinity, the CaSR is extremely sensitive to minute changes in extracellular [Ca ++ ]. The relationship between [Ca ++ ] and the rate of PTH secretion is described by a steep inverse sigmoidal curve. A 0.2-mM difference in blood [Ca ++ ] spans the full range of the curve, altering PTH secretion from basal (5% of maximum) to maximal levels ( Fig. 40.4 ). The steady-state “set point” will vary between individuals but typically resides below the midpoint of the curve (i.e., half-maximal PTH secretion). Thus the CaSR is a rapid, robust, and continuous regulator of PTH output in response to subtle [Ca ++ ] fluctuations.
![Fig. 40.4, Sigmoidal relationship between serum [Ca ++ ] and serum PTH, which reflects the rate of PTH secretion. PTH, Parathyroid hormone.](https://storage.googleapis.com/dl.dentistrykey.com/clinical/HormonalRegulationofCalciumandPhosphateMetabolism/2_3s20B9780323847902000400.jpg "Fig. 40.4, Sigmoidal relationship between serum [Ca ++ ] and serum PTH, which reflects the rate of PTH secretion. PTH, Parathyroid hormone.")
In addition to inhibiting PTH secretion, activation of the CaSR also promotes degradation of stored PTH in the parathyroid chief cell. As a result, biologically inactive carboxy-terminal PTH fragments are secreted from the parathyroid gland and are also produced by peripheral metabolism of PTH by the liver and kidney. Therefore, current PTH assays use two antibodies that recognize epitopes from both ends of the molecule to accurately measure intact PTH(1-84).
Over a longer time frame, PTH production is also regulated at the level of mRNA stability and gene transcription (see Fig. 40.3 ). Decreased [Ca ++ ] leads to production of proteins that bind the 3-untranslated region of PTH mRNA and stabilize it, leading to increased PTH translation. PTH gene transcription is repressed by 1,25-dihydroxyvitamin D in a negative feedback loop (acting through vitamin D response elements—see later). The ability of 1,25-dihydroxyvitamin D to hold PTH gene expression in check is reinforced by the coordinated upregulation of CASR gene expression by positive vitamin D response elements in the promoter region of the CASR gene (see Fig. 40.3 ). It should be noted, however, that during a hypocalcemic challenge, the decrease in [Ca ++ ] overrides the inhibitory effect of 1,25-dihydroxyvitamin D on PTH transcription, allowing both of these hormones to be elevated simultaneously.
IN THE CLINIC
Patients with benign familial hypocalciuric hypercalcemia (FHH) are heterozygous for inactivating mutations of the CaSR. In these patients, because of complete or partial loss of one CaSR allele, higher levels of [Ca ++ ] are required to suppress PTH secretion. This results in an elevated [Ca ++ ] set point for PTH secretion, accounting for the hypercalcemia. The CaSR is also expressed in the thick ascending limb of the renal tubule, where it normally inhibits Ca ++ reabsorption when blood Ca ++ rises. The hypocalciuria in the face of hypercalcemia in FHH is due to the reduced ability of the CaSR in the kidney to sense and respond to elevated blood [Ca ++ ] by increasing Ca excretion.
AT THE CELLULAR LEVEL
Parathyroid hormone–related peptide (PTHrP) is a peptide paracrine hormone produced by several adult tissues (skin, hair, breast), where it may regulate proliferation and differentiation. It also plays a role in relaxation of smooth muscle in response to stretch in blood vessels, uterus, and bladder. During lactation, PTHrP promotes maternal bone resorption and the transport of calcium into milk. During development, PTHrP regulates calcium transport across the placenta and is a key regulator of chondrocyte proliferation and differentiation in the growth plate of long bones. The 30 amino acids at the N-terminus of PTHrP have significant structural homology with PTH. PTHrP is not regulated by circulating Ca ++ and normally does not play a role in Ca/P i homeostasis in adults. However, certain tumors secrete high levels of PTHrP, which causes hypercalcemia of malignancy and symptoms that resemble hyperparathyroidism.
Parathyroid Hormone Receptor
The PTH receptor, designated PTHR1, binds both PTH and PTH-related peptide (PTHrP). It is expressed on osteoblasts and osteocytes in bone and in the proximal and distal tubules of the kidney to mediate the systemic actions of PTH. However, PTHR1 is also expressed in many developing organs where PTHrP has important paracrine functions. One such example is regulation of chondrocyte proliferation in the growth plate during endochondral bone growth.
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