Phosphate 1,2,5-dihydroxyvitamin

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Parathyroid hormone is a single-chain polypeptide of 84 amino acids which is produced in the parathyroid glands. It increases serum calcium and decreases serum phosphate. In bone it promotes resorption of calcium. It indirectly increases osteoclastic activity by promoting the action of osteoblasts. It has been shown that in low doses PTH may even increase bone formation without stimulating bone resorption. In the kidney PTH increases resorption of calcium and it increases excretion of phosphate. An other important activity in the kidney is the enhanced synthesis of 1,25-dihydroxyvitamin D. An increased serum calcium level inhibits PTH secretion and increased serum phosphate decreases free serum calcium and thus stimulates PTH secretion. 

Other target organs for the action of 1,25-dihydroxyvitamin D include the kidneys, bone, muscle,vwand skin. The hormone promotes reabsorption of both Ca2+ and inorganic phosphate by kidney tubules. In bone it binds to a specific receptor where it promotes the mobilization of calcium ions. This effect may result in part from stimulation of calcium-activated ATPase of the outer membrane of bone cells. Dissolution of bone also requires the presence of parathyroid hormone (PTH), the 83-residue hormone secreted by the parathyroid gland. In women past the age of menopause and in elderly men the production of 1,25-dihydroxyvitamin D decreases.w This may be a cause of the serious bone loss (osteoporosis) frequently observed. Treatment with 1,25-dihydroxyvitamin D3 or a synthetic analog seems to be helpful to such individuals. /Xy See also Chapter 30, Section A,5. 

Certain human populations depend on dietary sources of vitamin D because of insufficient biosynthesis of the vitamin due to inadequate skin exposure to sunlight. The classic symptoms of vitamin D deficiency are rickets in children and osteomalacia in adults. 25-Hydroxyvitamin D3 is the major circulating metabolite in the blood, but the hormonally active form of the vitamin is 1,25-dihydroxyvitamin D3. The latter metabolite stimulates the intestine to absorb calcium and phosphate by two independent mechanisms and acts with parathyroid hormone to mobilize calcium, accompanied by phosphate, from the bone fluid compartment into the bloodstream. 1,25-dihydroxyvitamin D 3 is also involved in the formation of osteoclasts—giant cells that are solely responsible for the resorption of bone matrix (33). Resorption is an essential process for the development, growth, maintenance, and repair of bone. 

Vitamin D. Vitamin D is a steroidlike hormone that can be obtained from dietary sources or synthesized in the skin from cholesterol derivatives in the presence of ultraviolet light. Vitamin D produces several metabolites that are important in bone mineral homeostasis.27,31 In general, vitamin D derivatives such as 1,25 dihydroxyvitamin D3 increase serum calcium and phosphate levels by increasing intestinal calcium and phosphate absorption and by decreasing renal calcium and phosphate excretion.27,46... 

Saito, H., Kusano, K., Kinosaki, M., Ito, H., Hirata, M., Segawa, H., Miyamoto, K. and Fukushima, N. (2003). Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1 alpha, 25-dihydroxyvitamin D3 production. J. Biol. Chem. 278, 2206-2211. 

Both the active and passive modes of calcium transport are increased during pregnancy and lactation. This is probably due to the increase in calbindin and serum PTH and 1,25-dihydroxyvitamin D concentrations that occur during normal pregnancy. Intestinal calcium absorption is also dependent on age, with a 0.2% per year decline in absorption efficiency starting in midlife. The fractional absorption of calcium depends on the form and dietary source. Absorption rates are 29% for the calcium in cow s milk, 35% for calcium citrate, 27% for calcium carbonate, and 25% for tricalcium phosphate. Other factors that limit the bioavailability of calcium in the intestine are oxalates and phy-tates, which are found in high quantities in vegetarian diets and which chelate calcium. 

Tissues contain two types of receptors for 1,25-dihydroxyvitamin D a classic steroid hormone nuclear receptor and a putative membrane receptor. 1,25-Dihydroxyvitamin D interacts with the nuclear receptor to form a receptor-ligand complex (Fig. 30-4). This complex then interacts with other nuclear proteins, such as the retinoic acid receptor (RXR) to form a functional transcription complex. The main effect of this transcription complex is to alter the amount of mRNAs coding for selected proteins such as cal-bindin, the calcium transport protein in the intestine, and the vitamin D receptor. In concert with PTH, 1,25-dihydroxyvitamin D acts to mobilize calcium from bone.As a consequence, serum calcium and phosphate homeostasis is maintained by a combination of 1,25-dihydroxyvitamin D stimulation of intestinal absorption and bone turnover. 

Biochemistry of Vtamin D Assessment of Vtamin D Status Action of 1 -Dihydroxyvitamin 03 in Regulating Transcriptkm Vitamin D Deficiency Phosphate Metabolism Treatment of Vitamin D Ddidency and Hazards of High Intake... 

Bone contains nearly all of the calcium (99%), most of the phosphate (85%), and much of the magnesium (55%) of the body. The concentrations of calcium, phosphate, and magnesium in plasma are dependent on the net effect of bone mineral deposition and resorption, intestinal absorption, and renal excretion. PTH and 1,25-dihydroxyvitamin D are the principal hormones regulating these three processes. 

Vitamin D is produced endogenously by exposure of skin to sunlight, and is absorbed from foods containing or supplemented with vitamin D. Vitamin D is metabolized to its biologically active form, 1,25-dihydroxyvitamin D (1,25[OH]2D), a hormone regulating calcium and phosphate metabolism. Deficiency of vitamin D results in impaired formation of bone, because of a mineralizing defect, producing rickets in children and osteomalacia in adults. 

Cross HS, Klaushoeee K and Peterlik M (1992) Triiodothyronine and 1,25-dihydroxyvitamin D actions and interactions at the gene, cell and organ level. In Bronner F, Peterlik M, eds. Extra and Intracellular Calcium and Phosphate Regulation. 

A number of hormones interact to regulate the and phosphate concentrations. The most important are PTH and 1,25-dihydroxyvitamin D (l,25-(OH)2D caldtriol), which regulate mineral homeostasis by effects on the kidney, intestine, and bone (Figure 61-3). 

FIGURE 61-5 Regulation of la-hydroxylase activity. Changes in the plasma levels of PTH, Ca, and phosphate modulate the hydroxylation of 25-OH vitamin D to the active form, 1,25-dihydroxyvitamin D. 

Kolek, O.I., Hines E.R., Jones M.D., et al. 2005. 1-alpha, 25-Dihydroxyvitamin D3 upregu-lates FGF23 gene expression in bone the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am. J. Physiol. Gastrointest. Liver Physiol. 289 ... 

Meng, Y. and Nemere, I. 2013. Effect of 24,25-dihydroxyvitamin D3 on phosphate absorption in vivo. Immunol. Endocrinol., and Met. Agents in Medic. Chem. 13 60-67. 

Nemere, I. 1996. Apparent nonnuclear regulation of intestinal phosphate transport Effects of 1,25-dihydroxyvitamin D3, 24,25-dihydroxyvitamin D3, and 25-hydroxy vitamin D3. Endocrinology 137 2254-61. 

Peery, S.L. and Nemere I. 2007. Contributions of pro-oxidant and anti-oxidant conditions to the actions of 24,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on phosphate nptake in intestinal cells./. Cell Biochem. 101(5) 1176—84. 

---