The High Calcium, High Phosphorus Rescue Diet Is Not Suitable to Prevent Secondary Hyperparathyroidism in Vitamin D Receptor Deficient Mice

Abstract The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)2D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1α-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)2D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1α-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.

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Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Journal of Biological Chemistry ◽

10.1074/jbc.m405562200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52406-52413 ◽

Cited By ~ 65

Author(s):

Wei Zheng ◽

Yixia Xie ◽

Gang Li ◽

Juan Kong ◽

Jian Q. Feng ◽

...

Keyword(s):

Vitamin D ◽

Secondary Hyperparathyroidism ◽

Vitamin D Receptor ◽

Calcium Homeostasis ◽

Critical Role ◽

Mineral Density ◽

Genetic Ablation ◽

High Calcium ◽

Calbindin D28k

Calbindin (CaBP)-D28k and CaBP-D9k are cytosolic vitamin D-dependent calcium-binding proteins long thought to play an important role in transepithelial calcium transport. However, recent genetic studies suggest that CaBP-D28k is not essential for calcium metabolism. Genetic ablation of this gene in mice leads to no calcemic abnormalities. Genetic inactivation of the vitamin D receptor (VDR) gene leads to hypocalcemia, secondary hyperparathyroidism, rickets, and osteomalacia, accompanied by 90% reduction in renal CaBP-D9k expression but little change in CaBP-D28k. To address whether the role of CaBP-D28k in calcium homeostasis is compensated by CaBP-D9k, we generated VDR/CaBP-D28k double knockout (KO) mice, which expressed no CaBP-D28k and only 10% of CaBP-D9k in the kidney. On a regular diet, the double KO mice were more growth-retarded and 42% smaller in body weight than VDRKO mice and died prematurely at 2.5–3 months of age. Compared with VDRKO mice, the double KO mice had higher urinary calcium excretion and developed more severe secondary hyperparathyroidism and rachitic skeletal phenotype, which were manifested by larger parathyroid glands, higher serum parathyroid hormone levels, much lower bone mineral density, and more distorted growth plate with more osteoid formation in the trabecular region. On high calcium, high lactose diet, blood-ionized calcium levels were normalized in both VDRKO and the double KO mice; however, in contrast to VDRKO mice, the skeletal abnormalities were not completely corrected in the double KO mice. These results directly demonstrate that CaBP-D28k plays a critical role in maintaining calcium homeostasis and skeletal mineralization and suggest that its calcemic role can be mostly compensated by CaBP-D9k.

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The effectiveness of nutritional vitamin D supplementation and selective vitamin D receptor agonists treatment on secondary hyperparathyroidism in chronic kidney diseases patients

Osteoporosis and Bone Diseases ◽

10.14341/osteo9879 ◽

2018 ◽

Vol 21 (2) ◽

pp. 12-22 ◽

Cited By ~ 1

Author(s):

Lilit V. Egshatyan ◽

Natalya G. Mokrisheva

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Secondary Hyperparathyroidism ◽

Vitamin D Receptor ◽

Vitamin D Supplementation ◽

Target Range ◽

Receptor Agonists ◽

Stage 4 ◽

Calcium Phosphorus ◽

Phosphorus Levels

Background: secondary hyperparathyroidism (SHPT) is an early complication of chronic kidney disease (CKD). Maintaining the level of 25(OH)D and parathyroid hormone concentrations in the target range reduce its associated complications (fractures and cardiovascular calcification). Aims: to examine the effectiveness of vitamin D supplementation and selective vitamin D receptor agonists treatment on SHPT in CKD. Material and methods: prospective observational study to evaluate the efficacy and safety of vitamin D therapy SHPT in 54 in patients with CKD. The first phase (24 weeks) – treatment of suboptimal 25-hydroxycalciferol (25(OH)D) levels. The second (16 weeks) – treatment colecalciferol-resistant SHPT by combination of cholecalciferol with paricalcitol. Blood samples were taken to assess parathyroid hormone (PTH), 25(OH)D, creatinine, calcium, phosphorus levels and calcium excretion. Results: After 8 weeks of cholecalciferol treatment all patients achieved 25(OH)D levels above 20 ng/ml, however 78% of patients still had SHPT. After 16 weeks, the decrease of PTH was achieved in all patients, but significantly only in patients with CKD 2 (19.2%, p< 0.01) and 3 (31%, p <0.05), compared with CKD 4 (17%, p >0.05). After 24 weeks of therapy, PTH normalized in all patients with CKD 2, in 15 (79%) with CKD 3 and in 9 (50%) patients with CKD 4. Cholecalciferol treatment resulted in a substantial increase in 25(OH)D levels with minimal or no impact on calcium, phosphorus levels and kidney function. After 24 weeks we initiated combination therapy (cholecalciferol and paricalcitol) for patients with colecalciferol-resistant SHPT (n=13). PTH levels decreased from 149.1±13.4 to 118.2±14.1 pg/ml at 8 weeks, and to 93.1±9.7 pg/ml (p <0.05) at 16 weeks of treatment. No significant differences in serum calcium, phosphorus or urinary calcium levels. Normalization of PTH was achieved in all patients with CKD 3 and in 8 patients with stage 4. One patient with CKD 4 needed an increase in paricalcitol dose. Conclusion: Cholecalciferol can be used in correcting vitamin D deficiency in patients with all stages of CKD, however, its effectiveness in reducing PTH in stage 4 is limited. Selective analogs, such as paricalcitol, were well-tolerated and effectively decreased PTH levels.

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The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection

Journal of Parasitology Research ◽

10.1155/2012/134645 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 18

Author(s):

James P. Whitcomb ◽

Mary DeAgostino ◽

Mark Ballentine ◽

Jun Fu ◽

Martin Tenniswood ◽

...

Keyword(s):

Vitamin D ◽

Immune Responses ◽

Vitamin D Receptor ◽

Leishmania Major ◽

Active Form ◽

Wild Type ◽

Vitamin D Signaling ◽

Deficient Mice ◽

Th 1

Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreasedLeishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance toL. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance toL. majorinfection but only in a host that is predisposed for Th-1 immune responses.

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