Hormonal Regulation of Calcium Balance Introduction Adequate amounts

Hormonal Regulation of Calcium Balance

Introduction • Adequate amounts of calcium in its ionized form, Ca+2, are needed for normal function of all cells • Body calcium ultimately is derived from the diet, and daily intake usually is offset by urinary loss • The skeleton acts as a major reservoir of calcium and can buffer the concentration of calcium in extracellular fluid by taking up or releasing calcium phosphate Dr. M. Alzaharna (2018)

Different Effects of Calcium • Calcium enters into a wide range of cellular and molecular processes • Changes of its concentration within cells regulate: – enzymatic activities – and fundamental cellular events as • • muscular contraction Secretion and cell division calcium and calmodulin also act as intracellular mediators of hormone action Dr. M. Alzaharna (2018)

Different Effects of Calcium – In the extracellular compartment, • calcium is vital for blood clotting • calcium may act in a hormone-like way as an extracellular regulator of a variety of cellular responses through stimulation of membrane calcium receptors – basic mineral of bones and teeth • Its concentration in extracellular fluid must be maintained within narrow limits • Deviations in either direction are not readily tolerated and, if severe, may be lifethreatening Dr. M. Alzaharna (2018)

Distribution of Calcium in the Body • The adult human body contains approximately 1, 000 grams of calcium, about 99% of which is sequestered in bone, primarily in the form of hydroxyapatite crystals (Ca 10(PO 4)6 (OH)2) • In addition to providing structural support, bone serves as an huge reservoir for calcium salts • Each day about 600 milligrams of calcium is exchanged between bone mineral and the extracellular fluid • Most of the calcium that is not in bone crystals is found in cells of soft tissues bound to proteins within the sarcoplasmic reticulum, mitochondria, and other organelles Dr. M. Alzaharna (2018)

Distribution of Calcium in the Body • Resting concentration of free calcium in cytosol at low levels of about 0. 1 μM – Cytosolic calcium can increase ten fold or more • The concentration of calcium in interstitial fluid is: – mainly of free, ionized calcium – 10% is complexed with such anions as citrate, lactate, or phosphate • Total calcium in blood plasma is normally about 10 mg/d. L – twice that of interstitial fluid – because calcium is avidly bound by albumin and other proteins Dr. M. Alzaharna (2018)

Calcium Balance • Normally, adults are in calcium balance; that is, on average, daily intake equals daily loss in urine and feces • Except for lactation and pregnancy, deviations from balance reflect changes in the metabolism of bone • Immobilization of a limb, bed rest and malignant disease are examples of circumstances that produce negative calcium balance • Whereas growth of the skeleton produces positive calcium balance Dr. M. Alzaharna (2018)

Dr. M. Alzaharna (2018)

Intestinal Absorption • Calcium is taken up along the entire length of the small intestine, but uptake is greatest in the duodenum and jejunum • Absorption of calcium requires metabolic energy and the activity of specific carrier molecules in the luminal membrane • Calcium is carried down by its concentration gradient into the cytosol of intestinal epithelial cells and is extruded from the basolateral surfaces in exchange for sodium, which must then be pumped out at metabolic expense • Overall transfer of calcium from the intestinal lumen to interstitial fluid proceeds against a concentration gradient Dr. M. Alzaharna (2018)

Bone • Crystallization or solubilization of bone mineral is determined by physicochemical equilibria related to the concentrations of calcium, phosphate, hydrogen, and other constituents in bone water • The fluxes of calcium and phosphate into or out of the bone extracellular fluid involve active participation of the cells of the bone membrane (endosteum, periosteum, osteocytes) • Hormones regulate the calcium concentration in the extracellular fluid compartment and the mineralization of bone by regulating the activities of these cells Dr. M. Alzaharna (2018)

Bone Dr. M. Alzaharna (2018)

Bone • Osteoblasts are the cells responsible formation of bone • During growth or remodeling of bone, some osteoblasts become entrapped in matrix and differentiate into osteocytes • Osteoclasts are responsible for bone resorption Dr. M. Alzaharna (2018)

Kidney • Ionized and complexed calcium pass freely through glomerular membranes • Normally 98 to 99% of calcium filtered by the glomeruli each day is reabsorbed by the renal tubules • two-thirds of the reabsorption occurs in the proximal tubule • Much of the remaining calcium is resorbed in the loop of Henle • Reabsorption of calcium in the area of the junction of the distal convoluted tubules and the collecting ducts is governed by an active, process • Active transport of calcium in this region is the principal target of hormonal regulation of calcium excretion Dr. M. Alzaharna (2018)

Phosphorus Balance • Because of their intimate relationship, the fate of calcium cannot be discussed without also considering phosphorus – Calcium usually is absorbed in the intestines accompanied by phosphorus, – and deposition and mobilization of calcium in bones always occurs in conjunction with phosphorus • About 90% of the 500 to 800 g of phosphorus in the adult human is deposited in the skeleton • Much of the remainder is incorporated into organic phosphates distributed throughout soft tissues in the form of phospholipids, nucleic acids, and soluble metabolites Dr. M. Alzaharna (2018)

Phosphorus Balance • The concentration of inorganic phosphate in blood is about 3. 5 mg/d. L – About 55% is present as free ions – about 35% is complexed with calcium or other cations – and 10% is protein-bound • Phosphate concentrations are not tightly controlled and may vary widely under such influences as diet, age, and sex • Ionized and complexed phosphate pass freely across glomerular and other capillary membranes Dr. M. Alzaharna (2018)

Parathyroid Glands and Parathyroid Hormone • Parathyroid hormone (PTH) is the principal regulator of the extracellular calcium pool • It increases the calcium concentration and decreases the phosphate concentration in blood by various direct and indirect actions on – bone, kidney, and intestine • In its absence, the concentration of calcium in blood, and hence interstitial fluid, decreases dramatically over a period of several hours while the concentration of phosphate increases Dr. M. Alzaharna (2018)

Parathyroid Glands and Parathyroid Hormone • Human beings typically have four parathyroid glands, but as few as two and as many as eight have been observed • Each gland is a flattened ellipsoid measuring about 6 millimeters in its longest diameter • The aggregate mass of the adult parathyroid glands is about 120 milligrams in men and about 140 milligrams in women • These glands adhere to the posterior surface of the thyroid gland or occasionally are embedded within thyroid tissue Dr. M. Alzaharna (2018)

Parathyroid Glands and Parathyroid Hormone • Parathyroid glands are comprised of two cell types – Chief cells • predominate and are arranged in clusters or cords • They are the source of PTH and have all the cytological characteristics of cells that produce protein hormones: – rough endoplasmic reticulum, prominent Golgi apparatus, and some membrane-bound storage granules Dr. M. Alzaharna (2018)

Parathyroid Glands and Parathyroid Hormone – Oxyphil cells, • which appear singly or in small groups • are larger than chief cells and contain a remarkable number of mitochondria • have no known function • thought by some to be degenerated chief cells • Their cytological properties are not characteristic of secretory cells, but they are sometimes able to produce small amounts of PTH • Few oxyphil cells are seen before puberty, but their number increases thereafter with age Dr. M. Alzaharna (2018)

Biosynthesis, storage and secretion of PTH • PTH is a simple straight-chain peptide of 84 amino acids (expressed as a larger 115 amino acid preprohormone) • PTH then is packaged into secretory granules • Synthesis of PTH is regulated at both transcriptional and at posttranscriptional sites – Cyclic AMP, acting through the cyclic AMP response element binding protein (CREB), upregulates PTH gene transcription, – whereas vitamin D (and high levels of intracellular calcium) downregulates transcription Dr. M. Alzaharna (2018)

Biosynthesis, storage and secretion of PTH • Parathyroid cells are unusual in the respect that hormone degradation as well as synthesis is adjusted according to physiological demand • As much as 90% of the hormone synthesized may be metabolized within the chief cells, which cleave PTH into fragments at an accelerated rate when plasma calcium concentrations are high • The ratio of fragments to intact hormone released into the circulation increases when plasma calcium is high and decreases when it is low Dr. M. Alzaharna (2018)

Physiological Actions of PTH: Actions on Bone • Increases in PTH concentration in blood result in mobilization of calcium phosphate from the bone matrix due primarily, and perhaps exclusively, to increased osteoclastic activity • Although activity of all bone cell types is affected by PTH, it appears that only cells of osteoblastic lineage express receptors for PTH • Osteoclasts and their precursors are thus not direct targets for PTH Dr. M. Alzaharna (2018) PTH acts on cells of osteoblastic lineage to stimulate production of M-CSF (macrophage colony stimulating factor) and RANKL (receptor activator of Nkappa B ligand), which results in osteoclast formation and activation

Physiological Actions of PTH: Actions on Bone • With prolonged continuous exposure to high concentrations of PTH, as seen with hyperparathyroidism, osteoclastic activity is greater than osteoblastic activity, and bone resorption predominates • In addition to its critical role in maintaining blood calcium concentrations, PTH is also important for skeletal homeostasis • As already mentioned, bone remodeling continues throughout life • Remodeling of bone not only ensures renewal and maintenance of strength, but also adjusts bone structure and strength to accommodate the various stresses and strains of changing demands of daily living – Increased stress leads to bone formation strengthening the affected area, – and weightlessness or limb immobilization leads to mineral loss Dr. M. Alzaharna (2018)

Physiological Actions of PTH: Actions on kidney • In the kidney, PTH produces three distinct effects, each of which contributes to the maintenance of calcium homeostasis • In the distal nephron: 1. It promotes the reabsorption of calcium • In the proximal tubule: 2. It inhibits reabsorption of phosphate 3. Promotes hydroxylation, and hence activation of vitamin D • In producing these effects, PTH binds to Gprotein coupled receptors in both the proximal and distal tubules and stimulates the production of cyclic AMP, diacylglycerol, and IP 3 Dr. M. Alzaharna (2018)

Physiological Actions of PTH: Effects on Intestinal Absorption • Calcium balance finally depends on intestinal absorption of dietary calcium • Calcium absorption is severely reduced in hypoparathyroid patients and dramatically increased in those with hyperparathyroidism • Intestinal uptake of calcium is stimulated by an active metabolite of vitamin D • PTH stimulates the renal enzyme that converts vitamin D to its active form, but has no direct effects on intestinal transport of either calcium or phosphate Dr. M. Alzaharna (2018)

Parathyroid hormone-related peptide (PTHr. P) • Closely related to PTH • PTHr. P bind with high affinity to the PTH receptor and therefore produce the same biological effects as PTH • Except during lactation little or no PTHr. P is found in blood plasma of normal individuals • Found in the plasma of patients suffering from certain malignancies and accounts for the accompanying hypercalcemia • PTHr. P thus appears to function in calcium homeostasis during lactation when secretion of milk may drain as much as 300 mg of calcium from the mother’s body each day Dr. M. Alzaharna (2018)

Regulation of PTH Secretion • Chief cells are exquisitely sensitive to changes in extracellular calcium and rapidly adjust their rates of PTH secretion in a manner that is inversely related to the concentration of ionized calcium • The resulting increases or decreases in blood levels of PTH produce either positive or negative changes in the plasma calcium concentration and thereby provide negative feedback signals for regulation of PTH secretion • The activated form of vitamin D, whose synthesis depends on PTH, is also a negative feedback inhibitor of PTH synthesis Dr. M. Alzaharna (2018)