Wednesday, May 22, 2013

HORMONES REGULATING MINERAL METABOLISM

REGULATION OF MINERAL METABOLISM:

PTH and 1, 25-dihydroxyvitamin D are the primary hormones regulating bone and mineral metabolism. Physiological role of calcitonin has not yet been established. PTHrP is the principal mediator of humoral hypercalcemia of malignancy.

PARATHYROID HORMONE

PTH (chromosome 11) is synthesized and secreted by parathyroid glands located posterior to thyroid gland. The glands consist of chief and oxyphil cells; the chief cells synthesize, store, and secrete PTH. It is cleared by liver and kidney. PTH acts directly on bone and kidney, and indirectly on intestine to regulate concentration of calcium and phosphate in plasma.

PTH is synthesized as pre-pro-PTH of 115 amino acids. These pre and pro segments are cleaved during their transport to GA where intact 84 amino acid PTH is formed. It is then stored, secreted or degraded intracellularly. PTH acts on the receptor and produce biological response like calcemic, phosphaturic and other response in kidney and bone. Oxidation of methionine residue at position 8 or 18 results in loss of biological activity. The middle portion of the molecule is quite immunogenic because of its hydrophobicity and species specificity. Further cleavage at C-terminal inactivates the hormone.

Free calcium in extracellular fluid is the main regulator of PTH synthesis, secretion and metabolism. Parathyroid gland responds to decrease in free calcium concentration within seconds. Calcium interacts with plasma membrane G protein coupled receptor in parathyroid cells; this leads to release of free calcium from intracellular stores and opening of membrane bound calcium channels. Hypercalcemia inhibits PTH synthesis and secretion and increases PTH metabolism whereas hypocalcemia has opposite effect.

1, 25-dihydroxyvitamin-D, phosphate and magnesium also influences the synthesis and secretion of PTH. Vitamin D interacts with vitamin D receptors in the parathyroid glands to chronically suppress PTH synthesis by suppressing PTH gene transcription and therefore secretion. Hyperphosphatemia and hypophosphatemia increase and decrease PTH synthesis and secretion respectively. Chronic severe hypomagnesemia such as in occurring in alcoholism has been associated with impaired PTH secretion, whereas acute hypomagnesemia may stimulate secretion. Hypermagnesemia suppress PTH secretion via the calcium sensing receptor in parathyroid gland.

PTH influences both calcium and phosphate homeostasis directly through its actions on both bone and kidney and indirectly on the intestine through 1, 25(OH)2D. PTH acts on its receptor and activates adenylyl cyclase producing cAMP, activation of kinase, phosphorylation of proteins, increased entry of calcium and releases intracellular calcium, stimulated phospholipase C activity with generation of DAG and phosphoinositide activated enzyme and transport systems, and secretion of lysosomal enzymes.

In the kidneys, PTH (1) induces 25-hydroxyvitamin D-1α-hydroxylase, increasing the production of 1, 25 (HO)2D, which stimulates intestinal absorption of both calcium and phosphate, (2) increases calcium reabsorption in the DCT of nephron, (3) decreases reabsorption of phosphate by PCT, and (4) inhibits Na+-H+ antiporter activity, which favors a mild hyperchloremic metabolic acidosis in hyperparathyroid states.
The effects of PTH on bone are chronic exposure to high concentration of PTH leads to increased bone resorption. It acts by altering the activity and number of osteoblasts and osetoclasts. Bone resorption a prompt effect, is important for maintenance of calcium homeostasis, whereas delayed effect are important for extreme systemic needs and skeletal homeostasis.

Thus all these conditions lead to increase in free and total calcium in serum but decreased phosphate. In urine inorganic phosphate and cAMP are increased. The increase in serum calcium reduces PTH secretion through a negative feedback loop, maintaining homeostasis.

Biologically active intact PTH is rapidly cleared from plasma (half-life<5 minutes) by metabolism to C-terminal fragments by liver and kidneys and cleared of intact PTH by kidneys. But rate of degradation of PTH decreases when calcium concentrations are low and increases when calcium is high.
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