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.
Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D 1,25(OH)(2)D, which can elicit calcium mobilization from bone when intestinal ...calcium absorption is decreased. The skeletal adaptations, however, are still poorly characterized. To gain insight into these issues, we analyzed the consequences of specific vitamin D receptor (Vdr) inactivation in the intestine and in mature osteoblasts on calcium and bone homeostasis. We report here that decreased intestinal calcium absorption in intestine-specific Vdr knockout mice resulted in severely reduced skeletal calcium levels so as to ensure normal levels of calcium in the serum. Furthermore, increased 1,25(OH)(2)D levels not only stimulated bone turnover, leading to osteopenia, but also suppressed bone matrix mineralization. This resulted in extensive hyperosteoidosis, also surrounding the osteocytes, and hypomineralization of the entire bone cortex, which may have contributed to the increase in bone fractures. Mechanistically, osteoblastic VDR signaling suppressed calcium incorporation in bone by directly stimulating the transcription of genes encoding mineralization inhibitors. Ablation of skeletal Vdr signaling precluded this calcium transfer from bone to serum, leading to better preservation of bone mass and mineralization. These findings indicate that in mice, maintaining normocalcemia has priority over skeletal integrity, and that to minimize skeletal calcium storage, 1,25(OH)(2)D not only increases calcium release from bone, but also inhibits calcium incorporation in bone.
The analysis of mice that lack systemically the actions of the active form of vitamin D, 1,25(OH)2 D, has shown that 1,25(OH)2 D is an essential regulator of calcium homeostasis and that its actions ...are aimed at maintaining serum calcium levels within narrow limits. Especially the stimulation of intestinal calcium transport by 1,25(OH)2 D is important for calcium and bone homeostasis. The involved transporters are however still elusive. The targeted deletion of 1,25(OH)2 D action in chondrocytes has provided compelling evidence for a paracrine control of bone development and endocrine regulation of phosphate homeostasis by 1,25(OH)2 D. Targeting vitamin D receptor (VDR) function in other tissues will further enhance our understanding of the cell-type specific action of 1,25(OH)2 D. In this review, we will discuss the current understanding and remaining questions concerning the calcemic actions of 1,25(OH)2 D in the intestine, kidney and bone, with special focus on the evidence obtained by the use of transgenic mouse models.
▸ 1,25(OH)2D promotes intestinal calcium transport during normal/low calcium intake. ▸ High 1,25(OH)2D levels minimize skeletal calcium content to maintain normocalcemia. ▸ High 1,25(OH)2D levels ...increase bone resorption leading to osteopenia. ▸ Increased VDR signaling in osteoblasts/osteocytes suppresses bone mineralization.
The serum calcium levels and the calcium content of the skeleton are highly interdependent. Indeed, bone requires calcium to preserve its strength, but it is at the same time also the predominant calcium storage from which calcium can be mobilized to supply the serum pool. The active form of vitamin D 1,25(OH)2D plays a crucial role in regulating the transfer of calcium between blood and bone, evidenced by experimental data obtained from systemic, intestinal-specific and osteocyte-specific vitamin D receptor (Vdr) null mice. In fact, 1,25(OH)2D is required to maintain normocalcemia and bone health by enhancing intestinal calcium absorption when dietary calcium intake is normal/low. When, however, insufficient calcium is absorbed via the intestine, 1,25(OH)2D levels will increase and will act on mature osteoblasts and osteocytes to minimize calcium levels in bone tissue in favor of the blood calcium pool. Mechanistically, the high 1,25(OH)2D levels enhance bone remodeling which leads to osteopenia, and suppress bone matrix mineralization by increasing the levels of mineralization inhibitors, which causes hyperosteoidosis and hypomineralization. Thus, depending on the intestinal calcium acquisition, 1,25(OH)2D will target the intestine and/or the skeleton to maintain calcium levels in serum within a normal range.
To study the role of the epithelial calcium channel transient receptor potential vanilloid type 6 (TRPV6) and the calcium-binding protein calbindin-D9k in intestinal calcium absorption, TRPV6 ...knockout (KO), calbindin-D9k KO, and TRPV6/calbindin-D9k double-KO (DKO) mice were generated. TRPV6 KO, calbindin-D9k KO, and TRPV6/calbindin-D9k DKO mice have serum calcium levels similar to those of wild-type (WT) mice (∼10 mg Ca2+/dl). In the TRPV6 KO and the DKO mice, however, there is a 1.8-fold increase in serum PTH levels (P < 0.05 compared with WT). Active intestinal calcium transport was measured using the everted gut sac method. Under low dietary calcium conditions there was a 4.1-, 2.9-, and 3.9-fold increase in calcium transport in the duodenum of WT, TRPV6 KO, and calbindin-D9k KO mice, respectively (n = 8–22 per group; P > 0.1, WT vs. calbindin-D9k KO, and P < 0.05, WT vs. TRPV6 KO on the low-calcium diet). Duodenal calcium transport was increased 2.1-fold in the TRPV6/calbindin-D9k DKO mice fed the low-calcium diet (P < 0.05, WT vs. DKO). Active calcium transport was not stimulated by low dietary calcium in the ileum of the WT or KO mice. 1,25-Dihydroxyvitamin D3 administration to vitamin D-deficient null mutant and WT mice also resulted in a significant increase in duodenal calcium transport (1.4- to 2.0-fold, P < 0.05 compared with vitamin D-deficient mice). This study provides evidence for the first time using null mutant mice that significant active intestinal calcium transport occurs in the absence of TRPV6 and calbindin-D9k, thus challenging the dogma that TRPV6 and calbindin-D9k are essential for vitamin D-induced active intestinal calcium transport.
Topical application of the vitamin D (VitD) analog calcipotriol is a highly effective standard treatment modality of psoriatic skin lesions. However, the immune modulatory effects of the treatment ...are incompletely understood. VitD is well known to induce tolerogenic responses in conventional dendritic cells (cDCs). Plasmacytoid DCs (pDCs) comprise a specialized, naturally occurring DC subset known to be important in autoimmune diseases including psoriasis. pDCs from the blood rapidly infiltrate psoriatic skin and are key to the initiation of the immune-mediated pathogenesis of the disease. We now demonstrate that pDCs express various proteins of the VitD receptor (VDR) pathway, including the VitD-metabolizing enzymes Cyp27B1 and Cyp24A1, and that VDR is transcriptionally active in pDCs. Moreover, VitD impairs the capacity of murine and human pDCs to induce T-cell proliferation and secretion of the T-helper 1 cytokine IFNγ. The inhibitory effect of VitD is dependent on the expression of the VDR in the DCs. This study demonstrates that VitD signaling can act as a natural inhibitory mechanism on both cDCs and pDCs, which may instigate the development of VitD-based therapeutic applications for psoriasis and other inflammatory skin diseases.
Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic ...chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expression is associated with impaired myeloid progenitor differentiation and is a new prognostic factor in AML. In mice, the lack of Vdr results in increased numbers of hematopoietic and leukemia stem cells and quiescent hematopoietic stem cells. In addition, malignant transformation of Vdr−/− cells results in myeloid differentiation block and increases self-renewal. Vdr promoter is methylated in AML as in CD34+ cells, and demethylating agents induce VDR expression. Association of VDR agonists with hypomethylating agents promotes leukemia stem cell exhaustion and decreases tumor burden in AML mouse models. Thus, Vdr functions as a regulator of stem cell homeostasis and leukemic propagation.
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•Transcriptional expression of VDR is associated with differentiation prognosis in AML•VDR expression is partially regulated by methylation•Combined use of hypomethylating agents and VD analog targets leukemic stem cells
Paubelle et al. show that targeting the vitamin D receptor has anti-leukemic activity by acting on cell differentiation and by decreasing stemness of AML cells.
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