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Serum Ca2+restored tonormalCa2+ PiCa2+Pi25(OH)D1␣-OHase6. PTH increasesreabsorption of Ca2+ anddecreasesreabsorption of Pi5b. 1,25(OH)2Dproduction increasedby high PTH andtransiently lowserum Ca2+7. PTH promotesosteoclastic resorption ofbone (Ca2+, Pi, and matrix)Ca2+PiUrineCa2+ lowPi high10. Bone resorption is net effectDietary Calcium Deficiency Inadequate dietary calcium intake (1) reduces plasma calcium concentration (2), which stimulates parathyroid hormone (PTH) secretion (3 and 4).
PTH increases the renal productionof active vitamin D (5) (which increases gut absorption of calcium) (8), increases renal calcium reabsorptionand decreases renal phosphate reabsorption (6), and increases bone resorption of calcium and phosphate(7). All of these mechanisms serve to increase the plasma calcium concentration to normal (9). Whenthere is a sustained calcium deficiency, the plasma calcium is maintained at a cost of severe bonedemineralization (10).Calcium-Regulating Hormones349Basal lamina of capillaryLumen of capillaryEndothelial cellDischarge of vesicle contentsinto perivascular spaceBasal lamina of chief cellNucleusEndoplasmic reticulumCell membraneSecretory vesiclesMitochondrionGolgi complexFigure 30.1 Parathyroid Hormone Secretion Parathyroid hormone is synthesized in the chief cellsof the parathyroid glands.
The active hormone is packaged in vesicles and stored in the cytoplasm untilreleased. PTH secretion is stimulated by small decreases in plasma calcium levels and provides rapidmobilization of calcium into the extracellular fluid.SYNTHESIS AND ACTIONS OF CALCIUMREGULATING HORMONESParathyroid HormoneSynthesis of Parathyroid HormoneParathyroid hormone (PTH) is the primary hormone regulating plasma calcium concentration. PTH is synthesized bythe chief cells of the parathyroid glands as a 110 amino acidpreprohormone (see Fig. 27.1). It is then cleaved to a prohormone in the endoplasmic reticulum and to the active 84amino acid peptide hormone in the Golgi apparatus. It is thenpackaged into secretory vesicles in the cytoplasm, and thevesicles stored until needed (Fig.
30.1).Actions of Parathyroid HormoneThe hormone is continually synthesized, and there is constantlow-level release of PTH into the blood. In response tosmall decreases in ionized calcium in the plasma, additionalPTH is released into the blood and acts at the intestines,bone, and kidney to restore plasma calcium to normal levels(Fig. 30.2). PTH stimulates cAMP through its G protein–coupled receptors:■At the kidney: (1) to increase calcium reabsorption atthe distal tubule, and to inhibit phosphate reabsorptionat both the proximal and distal tubules; and (2) toincrease the synthesis of 1,25-dihydroxycholecalciferol,the active metabolite of vitamin D.
This conversion iscritical to producing active vitamin D, and loss of PTHor loss of kidney function can impair vitamin D metabolism and function. The actions at the kidney are rapid■and are a main avenue for the rapid restoration of plasmacalcium levels.At the bone: To increase bone resorption, freeing calciuminto the blood. This occurs by osteocytic osteolysis,which rapidly (within 1 to 2 hours) mobilizes calciumfrom the unmineralized calcium phosphate pool, and byosteoclastic osteolysis, which breaks down mineralizedbone over about 12 hours. In response to more severe,prolonged decreases in plasma calcium (days to weeks),PTH can stimulate the proliferation of osteoclasts, tofurther break down mineralized bone. The end result isincreased calcium and phosphate in the plasma, at theexpense of loss of mineralization of bone.The chief cells of the parathyroid gland have calcium sensors,which monitor plasma calcium concentration.
This allowsrapid response when plasma calcium decreases, and PTH canquickly mobilize calcium from bone and stimulate vitamin Dproduction. Thus, PTH is crucial to the maintenance ofcalcium homeostasis.Parathyroid hormone–related protein (PTHrp) is aprotein that mimics the calcium-mobilizing effects ofPTH. It is present in a variety of tissues including smoothmuscle, breast, and the central nervous system and is believedto act in a paracrine manner. Although its normal actions arestill being investigated, PTHrp is also secreted from certaintumors, such as breast cancers and renal cell and squamous cellcarcinomas.350Endocrine PhysiologyCa2⫹ and Pi in foodVit.
DSunParathyroid hormone (PTH)Ultraviolet lightParathyroid glandsSkinVit. DVit. D, 25OHaseSerumandextracellularfluidInhibitionStimulationLiver25(OH)DCa2⫹PiCa 2⫹PiCa2⫹1,25(OH)2D1,25(OH)2D promotes absorptionof Ca2⫹ and Pi from intestinePi2⫹PiCa25(OH)DStimulation25(OH)D1␣-OHaseInhibition1,25(OH)2DCa2⫹PiPTHKidneyPTH increasesproduction of1,25(OH)2D, promotesCa2⫹ reabsorption, inhibitsPi reabsorption1,25(OH)2Dnecessaryfor normalmineralizationof boneCa2⫹PiPTH promotesosteoclasticresorption of bone(Ca2⫹, Pi, andmatrix)Figure 30.2 Parathyroid Hormone and Vitamin D Actions on Plasma Calcium Concentrations Parathyroid hormone (PTH) is secreted from the parathyroid glands in response to a decrease inplasma ionized Ca2+.
PTH acts rapidly (1) on bone to cause resorption and increase plasma Ca2+; and (2)on the kidney to increase Ca2+ reabsorption and decrease phosphate reabsorption and increase productionof active vitamin D. The increase in vitamin D increases Ca2+ absorption in the gut and promotes bone mineralization. Overall, the rapid effects of PTH increase Ca2+ in the blood, restoring homeostasis.Vitamin DSynthesis of Vitamin DVitamin D, or cholecalciferol, is a sterol that enters the bloodand extracellular fluid (ECF) from dietary sources and fromthe action of ultraviolet light on 7-dehydroxycholesterol inskin cells.
The initial form of vitamin D is converted to 25hydroxycholecalciferol in the liver and then undergoes finalhydroxylation to the active form, 1,25- dihydroxycholecalciferol, in the kidneys. Active vitamin D is bound to plasmaproteins and acts to increase plasma calcium concentrationand promote bone mineralization.Calcium-Regulating HormonesActions of Vitamin DWhen plasma calcium levels decrease, PTH increases andstimulates renal 1-α-hydroxylase to increase formation ofactive vitamin D.
The PTH will also increase resorption ofcalcium-phosphate from bone and increase renal calciumreabsorption, with the total effect of increasing plasma calciumlevels. Active vitamin D binds to its intracellular steroid receptor and acts:■■At the small intestine: To increase calcium absorptionby increasing apical calbindin (Ca2+-binding proteins)and increasing the basolateral Ca2+ ATPases. Thisenhances intestinal absorption of calcium.
Vitamin Dalso increases phosphate absorption, and excess plasmaphosphate is excreted by the kidneys (by PTH action).At the bone: To increase bone remodeling and mineralization through effects on both osteoblasts and osteoclasts. At high concentrations, vitamin D can cause bonedemineralization.lecalciferol concentrations in the plasma will remain constant,despite large increases in dietary vitamin D intake. In addition, the 25-hydroxycholecalciferol form can be stored in theliver for several months and released and converted to activevitamin D when needed, allowing another layer of regulationfor plasma levels of vitamin D. This overall control ofvitamin D levels is important, because overproduction ofactive vitamin D can actually cause bone resorption, insteadof deposition.CalcitoninCalcitonin is a 32 amino acid peptide hormone that is produced in the parafollicular cells of the thyroid gland, andalthough it appears to have effects on calcium handling, itdoes not contribute to the rapid regulation of calcium.
It isreleased in response to elevated plasma calcium levels and actson G protein–coupled receptors:■The synthesis and actions of vitamin D take time, but they actto increase the supply of calcium from the diet. Thus, whereasin the short-term plasma calcium levels are regulated by PTH,the activation of vitamin D by PTH is important in long-termcalcium homeostasis. When calcium levels are stabilized,calcium can be restored to the bone by the vitamin D.Active vitamin D levels in the blood are tightly regulated byfeedback control. Under normal conditions, 25-hydroxycho-351■At the kidney: To increase both calcium and phosphateexcretion.At the bone: To decrease bone resorption by reducingosteoclastic activity.It is not clear whether the physiologic effects of calcitonin areimportant in humans, because removal of the parafollicularcells has no dramatic effect on calcium homeostasis.352Endocrine Physiologyformation.
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