Calcitriol synthesis/response

Conditions associated with abnormalities in calcitriol synthesis or response can cause rickets in children and osteomalacia in adults. Specific disorders include X-linked hypophosphatemic rickets due to mutations in the PHEX endoprotease, Vitamin D-dependent rickets due to mutations in la-hydroxylase, and hereditary l,25-(OH)J) resistance due to mutations in the VDR. 

The active metabolite of vitamin D, calcitriol, is formed in the proximal tubules of the kidneys from calcidiol. There are three cytochrome P450-dependent enzymes in kidneys that catalyze 1-hydroxylation of calcidiol CYP27A and CYP27 in mitochondria and a microsomal la-hydroxylase, which is ferredoxin-dependent. It is likely that the microsomal enzyme is the most important its synthesis is induced by cAMP in response to parathyroid hormone (Section 3.2.8.2) and repressed by calcitriol (Omdahl et al., 2001 Wikvall, 2001). 

Synthesis ofthe vitamin D receptoris increased in response to bothparathy-roid hormone (Section 3.2.8.2) and calcitriol. It is not clear whether or not the... 

With the isolated perfused duodenum, there is a rapid increase in calcium transport in response to the addition of calcitriol to the perfusion medium. Isolated enterocytes and osteoblasts also show a rapid increase in calcium uptake in response to calcitriol. It is not associated with changes in mRNA or protein synthesis, but seems to be because of recruitment of membrane calcium transport proteins from intracellular vesicles to the cell surface. It is inhibited by the antimicrotubule compound colchicine. It can only be demonstrated in tissues from animals that are adequately supplied with vitamin D in vitamin D-deficient animals, the increase in intestinal calcium absorption occurs only more slowly, together with the induction of calbindin. 

Calcitriol modulates the maturation of chondrocytes via a cell surface receptor linked to phospholipase and protein kinase C in response to calcitriol, there are rapid changes in arachidonic acid release from, and reincorporation into, membrane phospholipids, and increased synthesis of prostaglandins Ei and E2 (Boyan et al., 1999). 24-Hydroxycalcidiol also modulates the maturation of chondrocytes, acting via cell surface receptors linked to phospholipase D, causing inactivation of both protein kinase C and MAP kinases, thus... 

Induction of Calbindin-D In response to calcitriol administration, there is an increase in mRNA synthesis and then in the synthesis of calbindin-D in intestinal mucosal cells, which is correlated with the later and more sustained increase in calcium absorption. In vitamin D-deficient animals, there is no detectable calbindin in the intestinal mucosa, whereas in animals adequately provided with vitamin D, it may account for 1 % to 3% of soluble protein in the cytosol of the colunmar epithelial ceils. Although the rapid response to calcitriol is an increase in the permeability of the brush border membrane to calcium, the induction of calbindin permits intracellular accumulation and transport of calcium. The rapid increase in net calcium transport in tissue from vitamin D-replete animals is presumably dependent on the calbindin that is already present in deficient animals, there can be no increase in calcium transport until sufficient calbindin has accumulated to permit intracellular accumulation, despite the increased permeability of the brush border. 

PTH is released in response to low serum calcium zmd induces the production of calcitriol. In contrast, reduced levels of PTH stimulate synthesis of the inactive 24,25-(OH)2D3. 

In thyroid cells in culture, calcitriol reduces production of cAMP in response to thyroid stimulating hormone by a nucletu action on the synthesis of G-protein subunits. However, it also reduces the responsiveness to cAMP, and attenuates cell growth and iodide uptake in response to thyroid stimulating hormone, with a rapid time course from direct action on protein kinase A (Berg andHaug, 1999). 

The vitamin D receptor (VDR/NR1I1) is a member of the superfamily of steroid hormone receptors. It regulates calcium homeostasis, cell proliferation, and differentiation, and exerts immunomodulatory and antimicrobial functions [119]. VDR binds to and mediates the calcemic effects of calcitriol (la,25-dihydroxy vitamin D3) after forming an heterodimer with RXR. la,25-dihydroxyvitamin D3 negatively regulates its own synthesis by repressing the 25-hydroxyvitamin D3 la-hydroxylase (CYP27B1) in a cell-type selective event that involves different combinations of multiple VDR response elements [120, 121]. 

Metabolic rickets and osteomalacia result from abnormality in synthesis of or response to calcitriol, the active form of vitamin D. 

Parathyroid hormone is secreted in response to a fall in plasma calcium. In the kidney it acts to increase the activity of calcidiol 1-hydroxylase and decrease that of the 24-hydroxylase. This is not an effect on protein synthesis, but the result of changes in the activity of existing enzyme protein, mediated by cAMP (section 10.3.2). In turn, both calcitriol and high concentrations of calcium repress the synthesis of parathyroid hormone. 

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