55 to 70% in children and young adults and from 20 to 45% in older men and women.
Kidney
In the kidney, Ca fluxes in the proximal tubule account for reabsorption of 65% of the filtered Ca, coupled to the bulk transport of solutes such as sodium and water [26].
About 20% of filtered Ca is reabsorbed in the cortical thick ascending limb of the loop of Henle (CTAL). In the CTAL, PTH binds to the PTH1R [27, 28], and enhances Ca reabsorption by increasing the activity of the Na/K/2Cl cotransporter that drives NaCl reabsorption and stimulates paracellular Ca and Mg reabsorption. The Ca sensing receptor (CaSR) is also present in the CTAL [29], where increased ECF Ca can bind and activate phospholipase A2, thereby reducing the activity of the Na/K/2Cl cotransporter and of an apical K channel, and diminishing paracellular Ca reabsorption. Consequently, a raised ECF Ca antagonizes the effect of PTH in this nephron segment and ECF Ca can in fact participate in this way as a hormone in the regulation of its own homeostasis.
About 15% of filtered Ca is reabsorbed in the distal convoluted tubule (DCT), where luminal Ca transfer into the renal tubule cell occurs via TRPV5, translocation of Ca across the cell from apical to basolateral surface involving proteins such as calbindin-D28K, and then active extrusion of the Ca from the cell into the blood via a Na+/Ca exchanger. PTH markedly stimulates Ca reabsorption in the DCT primarily by augmenting Na+/Ca exchanger activity via a cyclic AMP-mediated mechanism.
Bone
In bone, a major physiologic role of PTH appears to be to maintain normal Ca homeostasis by binding to PTH1R on cells of the osteoblast lineage and enhancing release of the cytokine, receptor activator of nuclear factor kB (NF-kB) ligand (RANKL) [30], which then binds to its receptor, RANK, on osteoclast precursors and osteoclasts, enhancing the formation of mature osteoclasts from precursors and augmenting the resorptive activity of existing osteoclasts, especially in cortical bone. PTH may also reduce the osteoblastic protein, osteoprotegerin, which binds to RANKL, forming an inactive complex, and preventing it from binding to RANK, thus reducing osteoclastic activity [31]. It has also been suggested that PTH can acutely release mineral at the bone surface in an osteoclast-independent manner by modifying its solubility [32]. PTH may also have anabolic effects via its action on osteoblastic cells, mainly on trabecular bone.
Vitamin D is essential for normal mineralization of bone via enhancing intestinal calcium and phosphate absorption and maintaining these ions within a range that facilitates hydroxyapatite deposition in bone matrix. A major direct function of 1,25(OH)2D may also be to act directly on bone to enhance osteoclastic bone resorption by increasing the RANKL/OPG ratio in order to enhance the proliferation, differentiation, and activation of the osteoclastic system [33, 34]. High levels of 1,25(OH)2D may also inhibit mineralization. Endogenous and exogenous 1,25(OH)2D have also been reported to have an anabolic role in vivo [35, 36].
Integrated Hormonal Action in Regulating ECF Calcium
Classic endocrine feedback loops ensure the minute-to-minute regulation of blood Ca. Extracellular Ca binds and activates the CaSR on the surface of parathyroid cells. The CaSR is coupled to the G-proteins Gi and Gq/11 and its activation by ECF Ca lead to a decrease in intracellular cAMP and an increase in intracellular calcium and diacyl glycerol. The increase in intracellular Ca leads to a reduction in the release of PTH. Hypocalcemia leads to the opposite sequence of events.
Thus, a decrease in ECF Ca leads to reduced activation of the parathyroid CaSR, which leads to lower intracellular Ca, and an increase in PTH production and secretion (Fig. 2). PTH can rapidly (over the course of minutes) augment Ca reabsorption in the CTAL and DCT of the kidney. PTH then acts on bone, over the course of several hours to days, to enhance osteoclastic bone resorption and liberate both Ca and phosphate from the skeleton. PTH has also been reported to increase the release of FGF23 from mature osteoblasts and osteocytes [37]. There may also be PTH-independent “buffering” of ECF Ca by bone through incompletely understood mechanisms, perhaps involving the CaSR, which rapidly returns ECF Ca to its baseline value following the induction of hypocalcemia [38]. PTH can stimulate the renal conversion of 25(OH)D, to the active sterol 1,25(OH)2D [39], likely over several hours, which in turn will augment intestinal Ca absorption. More prolonged hypocalcemia and exposure to elevated PTH, may also result in 1,25(OH)2D-mediated release of Ca and P from bone [40]. The net effect of the increased reabsorption of filtered Ca along the nephron, of the mobilization of Ca from bone, and of the increased absorption of Ca from the gut is to restore the ECF Ca to normal and to inhibit further production of PTH and 1,25(OH)2D. Additionally, FGF23 can be released from bone by 1,25(OH)2D [41] and can in turn reduce 1,25(OH)2D concentrations [42]. FGF23 has also been reported to decrease PTH production, thereby further ensuring that Ca homeostasis is restored [43, 44].
When the ECF Ca is raised into the hypercalcemic range, the opposite sequence of events occurs, that is, PTH secretion is reduced due to the stimulation of the parathyroid CaSR, and renal 1,25(OH)2D production is decreased. In addition, the elevated Ca per se may stimulate the renal CaSR in the CTAL, thus inducing calciuria. Therefore, the effect of suppressing PTH release and 1,25(OH)2D synthesis and of stimulating renal CaSR results in reduced renal tubular Ca reabsorption, decreased skeletal Ca release, and decreased intestinal Ca absorption, resulting in the normalization of the elevated ECF Ca.
References
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