Calcium homeostasis and role of parathyroid hormone (PTH), vitamin D and calcitonin: Calcium balance is influenced by dietary intake, intestinal absorption, renal excretion, and bone remodeling. Blood calcium levels are not a good indicator of total body calcium stores because more than 99% of calcium is stored in bone. In addition to its role in bone formation, calcium is essential for many body functions, including extra- and intracellular signaling, nerve impulse transmission, and muscle contraction.
Serum ionized calcium is the metabolically active form, and its level is tightly regulated in the bloodstream. The main calcium-binding proteins include albumin and globulin in serum, and calmodulin and other calcium-binding proteins inside cells.
Bone balance changes across the lifespan:
PTH: PTH is secreted by the chief cells of the parathyroid gland. Parathyroid cell membranes contain a Ca+±sensing receptor (CaSR), a GPCR linked to Gq.
Magnesium also affects PTH:
PTH receptor: The PTH receptor (PTHr) is located on the renal PCT and DCT and on osteoblasts in bone. It is a G protein-coupled receptor with seven membrane-spanning helices. Ligands can activate at least two second-messenger signaling systems in PTHr:
Both PTH and PTHrp (PTH-related peptide) bind to the same receptor.
PTH effects: When blood calcium is low, PTH is secreted into the circulation and acts primarily on the kidney and bone by binding to cells that express PTHr.
In the kidney:
In bone:
PTH action on osteoblasts changes the synthesis and/or activity of several proteins, including osteoclast-differentiating factor, also known as TRANCE (tumor necrosis factor-related activation-induced cytokine), RANKL, or osteoprotegerin (OPG) ligand. PTHr are located on osteoblasts.
PTH also increases expression of several bone-resorbing cytokines in osteoblasts, such as OPG ligand (OPGL), M-CSF, and TRAIL.
Calcitonin: Calcitonin is produced by the parafollicular © cells of the thyroid. It signals by binding to its receptor (CTR) on the plasma membrane of effector cells. Calcitonin binding to CTR activates multiple G-protein-mediated signaling pathways, including:
Calcitonin is released in response to hypercalcemia.
Like PTH, calcitonin increases Vit D synthesis by stimulating transcription of the 1α-hydroxylase gene in the proximal tubule of the kidney. Circulating calcitonin levels are elevated during pregnancy and lactation, which protects the maternal skeleton from excessive resorption during lactation.
Synthesis: Vitamin D3 (cholecalciferol) is generated in the skin from 7-dehydrocholesterol after exposure to sunlight. The plant form is vitamin D2 (ergocalciferol). Vitamin D (either D3 or D2) has little biological activity on its own.
The active form is 1,25-dihydroxycholecalciferol (1,25-dihydroxy vit D), a steroid hormone. It is produced in two hydroxylation steps:
25(OH) vitD is transported to the kidney, where it is internalized by megalin, a transmembrane protein that acts as a surface receptor for Vit D binding protein. In the proximal renal tubule, 25(OH)D3 is hydroxylated by 1α-hydroxylase (CYP27B1) to form 1,25(OH)2D3.
A serum concentration of 25-hydroxyvitamin D is the best indicator of vitamin D status because it is the major circulating form. The half-life of 25(OH)D3 is several weeks, while the half-life of 1,25-dihydroxy vit D is only a few hours.
Vit D can also be hydroxylated at C-24 to form 24,25 dihydroxy vit D, which is not physiologically active.
Vit D receptor: The genomic actions of 1,25(OH)2D3 are mediated by the vitamin D receptor (VDR). When 1,25(OH)2D3 binds VDR, the receptor heterodimerizes with the retinoid X receptor. Together with co-regulatory proteins, this complex interacts with vitamin D response elements in and around target genes and regulates transcription.
VDR is expressed in all segments of the small and large intestine. Vitamin D receptors are present in most cells in the body.
Actions of vit D: In the intestine, Vit D increases calcium absorption by inducing expression of:
TRPV6 is an apical brush border channel in enterocytes that supports Vit D-dependent Ca++ absorption. Calbindin helps move calcium through the enterocyte and buffers intracellular calcium to prevent toxic accumulation. CaATPase pumps Ca++ across the basolateral membrane into the bloodstream. In this way, 1,25(OH)2D3 controls calcium entry, intracellular binding/transport, and basolateral extrusion.
Vit D also stimulates intestinal absorption of phosphate and magnesium ions.
In the distal tubule of the kidney, 1,25(OH)2D3 regulates transcellular calcium transport in a similar way by inducing calbindins and the epithelial calcium channel TRPV5, which facilitates apical calcium entry. It increases reabsorption of both calcium and phosphate in the renal tubules.
In bone, Vit D promotes osteoclast activity, supporting bone resorption to increase blood Ca++ levels. At the same time, it promotes bone mineralization and formation of osteoid and new bone. Overall, Vit D influences bone remodelling by promoting resorption of old bone while stimulating new bone formation.
Vit D induces synthesis of osteocalcin. Osteocalcin is a protein hormone secreted by osteoblasts. It is involved in bone turnover and in energy, lipid, and carbohydrate metabolism. Lower osteocalcin levels are seen in metabolic syndrome and insulin resistance.
Vitamin D also has potent effects on the growth and differentiation of many cell types, including immune cells.
Regulation of Vit D: The activity of 1-alpha-hydroxylase in the kidney is tightly regulated and is the major control point for production of active Vit D.
When the need for Ca++ is lower, the inactive 24,25 dihydroxy vit D form is higher. When the need for Ca++ is higher (for example, in hypocalcemia), 1,25 dihydroxy vit D is preferentially synthesized.
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