The main reason for step one,25(OH)
The genomic actions of 1,25(OH)2 are mediated by the vitamin D receptor (VDR). 1,25(OH)2-occupied VDR heterodimerizes with the retinoid X receptor and together with co-regulatory proteins interacts with vitamin D response elements in and around target genes and mediates their transcription. 21,22
2 in the maintenance of calcium homeostasis is to increase calcium absorption from the intestine (Figure 1). 2 calcium absorption has been reported in the distal as well as the proximal intestine. 4 Rickets and osteomalacia are prevented when VDR null mice are fed a diet high in go to site calcium and lactose, indicating that 1,25(OH)2 and VDR have a critical role in bone mineralization by regulating intestinal calcium absorption. 2step three,24 1,25(OH)2 has been reported to regulate every step of the intestinal transcellular calcium transport process. It induces the expression of the apical membrane calcium channel TRPV6, the calcium-binding protein calbindin-D9k (it has been suggested that calbindin facilitates, in part, translocation of calcium through the enterocyte and buffers calcium preventing toxic levels of calcium from accumulating in the cell), and the plasma membrane CaATPase, PMCA1b. Thereby, 1,25(OH)2 exerts its control in the intestine on calcium entry, calcium binding, and basolateral extrusion of calcium. 4
When serum calcium is low, 1,25(OH)2 and parathyroid hormone (PTH) act to maintain calcium homeostasis. 1,25(OH)2-the active form of vitamin D and the ligand for the vitamin D receptor (VDR)-acts to increase calcium absorption from the intestine. If normal calcium is unable to be maintained by intestinal calcium absorption, then 1,25(OH)2 and PTH, together acting via their receptors, release calcium from the bone stores and increase reabsorption of calcium from the distal tubule of the kidney.
Although the expression of calbindin-D9k and TRPV6 is regulated by 1,25(OH)2, calbindin-D9k or TRPV6 null mice actively transport calcium similar to wild-type mice in response to 1,25(OH)2, suggesting that other calcium channels or binding proteins can contribute to the calcium transport process in their absence as a compensatory mechanism. 25 However, increased bone turnover and impaired bone mineralization have been observed in TRPV6 null mice that are maintained on a low-calcium diet. 26 Moreover, overexpression of TRPV6 in the mouse intestine results in hypercalciuria, hypercalcemia, and soft tissue calcification, indicating a significant role for TRPV6 in intestinal calcium absorption. 27 In addition, our studies using calbindin-D9k/TRPV6 double knockout mice revealed that when both genes are absent calcium absorption in response to low dietary calcium is least efficient, suggesting that calbindin-D9k and TRPV6 can act together in certain aspects of the active transcellular calcium transport process. 25
If normal serum calcium cannot be maintained by intestinal calcium absorption, then 1,25(OH)2 acts together with PTH to increase calcium reabsorption from the renal distal tubule and to remove calcium from bone (Figure 1). In the distal tubule of the kidney, similar to the intestine, 1,25(OH)2 regulates the transcellular transport process by inducing an epithelial calcium channel TRPV5 (75% sequence homology with TRPV6), which facilitates apical calcium entry, and by inducing the calbindins (calbindin-D9k and calbindin-D28k are both present in mouse kidney; only calbindin-D28k is present in rat and human kidney). 28,29 Extrusion of calcium at the distal tubule is via PMCA1b and the Na + /Ca 2+ exchanger. Although it has been a matter of debate, studies in Cyp27b1 null mice have shown that the Na + /Ca 2+ exchanger is decreased, suggesting regulation of the Na +/ Ca 2+ exchanger as well as the calbindins and TRPV5 by 1,25(OH)2. 30 The importance of TRPV5 in renal calcium reabsorption was noted in studies in TRPV5 null mice. TRPV5 null mice display severe hypercalciuria and significant changes in the bone structure. 31 In bone, both PTH and 1,25(OH)2 stimulate osteoclastogenesis. 22 Osteoclastic bone resorption results in the release of calcium from bone to maintain calcium homeostasis.