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The regulation of calcium is achieved mostly through the actions of 2 hormones: the active form of vitamin D 1,25-(OH)2D and parathyroid hormone (PTH), a peptide hormone produced by the parathyroid glands The active form of vitamin D acts mainly to stimulate intestinal absorption of calcium and phosphate In growing children, this ensures a supply of substrate for bone formation, and in adults it ensures a supply to replace the ongoing dissolution of bone PTH has several actions, a key one being to dissolve bone and move calcium into the blood PTH stimulates the bone membrane to release calcium on a short-term basis, and via paracellular signals from osteoblasts, also stimulates osteoclasts to resorb bone (Figure 10 2) These processes protect the body from low-calcium tetany Simply stated, the active form of vitamin D regulates what comes into the body and PTH regulates what is in the ECF
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The term vitamin D denotes a family of closely related molecules that are derived from cholesterol One member of this family, called vitamin D3 (cholecalciferol), is synthesized by the action of ultraviolet radiation on 7-dehydrocholesterol in the skin The 7-dehydrocholesterol precursor is normally present in adequate amounts to avoid limiting the production of vitamin D3 Thus, the synthesis of vitamin D3 itself is strongly dependent on exposure to sunlight, which is, in turn, dependent
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Figure 10 2 Mechanism of calcium reabsorption The distal convoluted tubule is the major site for regulated reabsorption Ca enters via apical Ca channels (under the control of parathyroid hormone [PTH]) and is actively transported across the basolateral membrane via Na-Ca antiport and via a Ca-ATPase The apical membrane also contains the NaCl symporter (NCC), which is the target for inhibition by thiazide diuretics Interestingly, the inhibition of NCC with thiazide diuretics promotes calcium reabsorption (probably by enhancing the basolateral sodium gradient and increasing Na-Ca exchange) Thus, thiazides may reduce the calcium loss associated with osteoporosis
regulation of CalCium and phosphate balanCe / 193
on climate, latitude, clothing, and so on Vitamin D3, like cholesterol, is a 27carbon molecule containing 1 hydroxyl group Another member of the family is vitamin D2, which is ingested in food, specifically food derived from plants Vitamin D2 (ergocalciferol) differs chemically from vitamin D3 by an additional methyl group and a double bond between 2 of the carbons It is a form of vitamin D often added as a supplement to foods These 2 members of the vitamin D family act by identical mechanisms, although vitamin D3 is more potent Vitamin D means either vitamin D2 or vitamin D3 Vitamin D as such is inactive (ie, neither ingested vitamin D2 nor the vitamin D3 formed in the skin has any significant biological activity) It must undergo metabolic changes within the body before it can influence its target cells Circulating vitamin D is hydroxylated at the 25 position by the liver and then hydroxylated again at the 1 position by proximal tubular cells within the kidneys to yield a cholesterol derivative containing 3 hydroxyl groups (When formed from vitamin D3, it is called calcitriol) This dihydroxy form of vitamin D 1,25dihydroxyvitamin D, or 1,25-(OH)2D exerts actions on target cells From this description, it should be evident that the molecular species that is actually exerting actions on target tissues is a hormone, not a vitamin, because it is made in the body Therefore, we usually call this hormone the active form of vitamin D Because the active form is generated in the renal epithelium, the kidneys are major regulators of calcium homeostasis in the GI tract and bone as well as regulators via urinary excretion The major action of vitamin D is to stimulate active absorption of calcium and phosphate by the intestine A role of vitamin D is to stimulate synthesis of the proteins involved in the steps described earlier In addition, vitamin D has some independent actions on bone that are not entirely clear As well, it stimulates the renal-tubular reabsorption of calcium and phosphate, again by increasing the synthesis of the protein components in the transport pathway The influences of vitamin D on bone and the kidney are far less important than its actions on the GI tract to stimulate absorption of calcium and phosphate The major event in vitamin D deficiency is decreased gut calcium absorption, resulting in decreased availability of calcium for bone formation or reformation In children, the newly formed bone protein matrix fails to be calcified normally because of the low availability of calcium, leading to the disease rickets
PTH (parathyroid hormone) is an 84-amino peptide hormone secreted by the parathyroid glands The GI tract, kidneys, and bone are all subject to direct or indirect control by PTH It is a substance essential for life, for without PTH, plasma calcium falls to lethal levels within a few days All of its normal activity is contained in the first 34 amino acids, and synthetic PTH can be made containing only this component The PTH half-life in the plasma is very short (<10 min), mostly due to rapid degradation in the liver,5 with renal filtration and uptake
5 In breaking down PTH, the liver releases peptide fragments that are active hormones in their own right, but with actions different from PTH These fragments act to oppose the normal actions of PTH
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