Pth

Parathyroid Glands and Parathyroid Hormone

FIGURE 7 Effects of PTH in the activation of osteoclasts and osteoblasts. M-CSF, macrophage colony stimulating factor; RANKL, receptor activator of N-srB ligand. PTH stimulates osteoblastic cells in the bone marrow to secrete M-CSF and to express RANKL on their surface. Contact with osteoclast precursors initiates their transformation to osteoclasts, which digest bone matrix and release previously sequestered growth factors that stimulate osteoblasts to lay down new bone.

Osteoclast Precursor

FIGURE 7 Effects of PTH in the activation of osteoclasts and osteoblasts. M-CSF, macrophage colony stimulating factor; RANKL, receptor activator of N-srB ligand. PTH stimulates osteoblastic cells in the bone marrow to secrete M-CSF and to express RANKL on their surface. Contact with osteoclast precursors initiates their transformation to osteoclasts, which digest bone matrix and release previously sequestered growth factors that stimulate osteoblasts to lay down new bone.

for binding RANKL. PTH also induces retraction of osteoblastic lining cells and thus exposes bony surfaces to which osteoclasts can bind.

Synthesis and secretion of collagen and other matrix proteins by osteoblasts are inhibited in the early phases of PTH action, but are reactivated subsequently as a result of the biological coupling discussed earlier, and new bone is laid down. At this time PTH stimulates osteoblasts to synthesize and secrete growth factors including insulin-like growth factor I (IGF-I) and transforming growth factor ft (TGFft), which are sequestered in the bone matrix and also act in an autocrine or paracrine manner to stimulate osteoblast progenitor cells to divide and differentiate. At least part of the stimulus for osteoblastic activity that follows osteoclastic activity may come from liberation of growth factors that were sequestered in the bony matrix when the bone was laid down. With prolonged continuous exposure to high concentrations of PTH, as seen with hyperparathyroidism, osteoclastic activity is greater than osteoblastic activity, and bone resorption predominates. However, intermittent stimulation with PTH leads to net formation of bone.

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, while weightlessness or limb immobilization leads to mineral loss. Osteocytes entrapped in the bony matrix are thought to function as mechanosensors that signal remodeling through release of prostaglandins, nitric oxide, and growth factors. In animal studies these actions are facilitated and enhanced by 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 it promotes the reabsorption of calcium, and in the proximal tubule it inhibits reabsorption of phosphate and promotes hydroxylation and, hence, activation of vitamin D (see later discussion). In producing these effects, PTH binds to G-protein-coupled receptors in both the proximal and distal tubules and stimulates the production of cyclic

AMP, DAG, and IP3. Some cyclic AMP escapes from renal tubular cells and appears in the urine. About one-half of the cyclic AMP found in urine is attributable to renal actions of PTH.

Calcium Reabsorption

The kidney reacts quickly to changes in PTH concentrations in blood and is responsible for minute-to-minute adjustments in blood calcium. PTH acts directly on the distal portion of the nephron to decrease urinary excretion of calcium well before significant amounts of calcium can be mobilized from bone. About 90% of the filtered calcium is reabsorbed in the proximal tubule and the loop of Henle independently of PTH. Therefore, because its actions are limited to the distal reabsorptive mechanism, PTH can provide only fine-tuning of calcium excretion. Even small changes in the fraction of calcium reabsorbed from the glomerular filtrate, however, can be of great significance. Hypopara-thyroid patients whose blood calcium is maintained in the normal range excrete about three times as much urinary calcium as normal subjects.

The cellular mechanisms that account for increased calcium reabsorption in response to PTH are shown in Fig. 8. Activation of G-protein-coupled receptors on the basolateral surface of cells in the distal convoluted tubules causes intracellular vesicles that harbor calcium channels to migrate to the luminal surface and fuse with the luminal membrane. Calcium ions in tubular fluid flow passively down their concentration gradient into the cells.

FIGURE 8 Effects of PTH on calcium reabsorption in the distal nephron. Gsa, a-subunit of the stimulatory G protein; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.

In the basolateral membrane PTH activates sodium calcium antiporters that exchange three ions of extracellular sodium for one ion of intracellular calcium, a calcium ATPase that pumps calcium across the membrane, and the sodium potassium ATPase that maintains the electrochemical gradient across the membrane. Even when maximally stimulated, this PTH-sensitive mechanism has a low capacity that saturates when the filtered load of calcium is high. The filtered load of calcium is determined in part by the plasma calcium concentration and, hence, may increase with continued increased secretion of PTH. Because reabsorption of calcium in the proximal portions of the nephron is proportional to sodium and water reabsorption, a nearly constant fraction of the filtered load reaches the distal nephron. Consequently when the filtered load is high, more calcium may reach the distal nephron than the reabsorb-ing mechanism can handle. This circumstance accounts for the paradoxical increase in urinary calcium seen in later phases of PTH action. Regardless of the absolute amount excreted, however, PTH decreases the fraction of filtered calcium that escapes in the urine.

Phosphate Excretion

Parathyroid hormone powerfully inhibits tubular reabsorption of phosphate and thus increases the amount excreted in urine. This effect is seen within minutes after injection of PTH and is exerted in the proximal tubules, where the bulk of phosphate reabsorption occurs. Decreased reabsorption of phosphate results from decreased capacity for sodium-phosphate cotransport across the luminal membrane of tubular cells. In a manner analogous—but opposite—to its effects on calcium reabsorption, PTH decreases the abundance of sodium-phosphate cotransporters in the brush border of proximal tubule cells by stimulating their translocation to intracellular vesicles (Fig. 9).

Effects on Intestinal Absorption

Calcium balance ultimately depends on intestinal absorption of dietary calcium. Calcium absorption is severely reduced in hypoparathyroid patients and dramatically increased in those with hyperparathyroidism. Within a day or two after treatment of hypoparathyroid subjects with PTH, calcium absorption increases. 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 (see Fig. 9 and later discussion), but has no direct effects on intestinal transport of either calcium or phosphate.

Proximal Tubular Cell

FIGURE 9 Effects of PTH on proximal tubule cells. PT, sodium phosphate cotransporter. 25OHD3 and 1,25(OH)2D3 are metabolic forms of vitamin D (see Fig. 15). Gsa, a-subunit of the stimulatory G protein; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cyclic AMP response element binding protein.

Proximal Tubular Cell

Lumen

FIGURE 9 Effects of PTH on proximal tubule cells. PT, sodium phosphate cotransporter. 25OHD3 and 1,25(OH)2D3 are metabolic forms of vitamin D (see Fig. 15). Gsa, a-subunit of the stimulatory G protein; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cyclic AMP response element binding protein.

Regulation of PTH Secretion

Chief cells of the parathyroid glands 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 (Fig. 10). 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 (see later discussion). Although blood levels of phosphate are also affected by PTH, high phosphate appears to exert little or no effect on the secretion of PTH, but may exert some effects on hormone synthesis. Under experimental conditions, high concentrations of magnesium in plasma may also inhibit PTH secretion, but the concentration range in which magnesium affects secretion is well beyond that seen physiologically. A decrease in ionized calcium in blood appears to be the only physiologically relevant signal for PTH secretion.

Chief cells are programmed to secrete PTH unless inhibited by extracellular calcium, but secretion is not totally suppressed even when plasma concentrations are very high. Through mechanisms that are not understood, normal individuals secrete PTH throughout the day in pulses with frequencies of one to three pulses per hour. Blood levels of PTH also follow a diurnal pattern with peak values seen shortly after midnight and minimal values seen in late morning. Diurnal fluctuations appear to arise from endogenous events in the chief cells and may promote anabolic responses of bone to PTH.

The cellular mechanisms by which extracellular calcium regulates PTH secretion are poorly understood. These cells are equipped with calcium-sensing receptors in their plasma membranes and can adjust secretion in response to as little as a 2-3% change in extracellular calcium concentration. Calcium-sensing receptors are members of the G-protein-coupled receptor superfamily (see Chapter 2) and bind calcium in proportion to its concentration in extracellular fluid. Because they appear to be coupled to adenylyl cyclase through Gi, and to phospholipase C, and perhaps membrane calcium channels probably through Gq, several second messengers appear to be involved in governing PTH secretion. Increased extracellular calcium increases production of DAG and IP3 and decreases production of cyclic AMP. Cytosolic calcium increases as a result of IP3-mediated release from intracellular stores followed by influx

43. Hormonal Regulation of Calcium Metabolism f

FIGURE 10 Regulation of PTH secretion. (—), decrease; ( + ),

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