The Adipocyte Renin Angiotensin System Mediates the Effects of Calcitriol on Oxidative Stress Norman AW, Song X, Zanello L, Bula C, Okamura WH. In addition, calcitriol activated Akt in cardiomyocytes and Mizwicki, M. T., Keidel , D., Bula, C. M., Bishop, J. E., Zanello, L. P., Wurtz, J. M., et al. Calcitriol’s effect to genomically control the synthesis of parathyroid hormone. ( Adapted from Chew DJ Bula G, Koziolek H, Niemiec A, et al.
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However, apart from these traditional calcium-related actions, 1, OH 2 D 3 and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities.
Physiological and pharmacological actions of 1, OH 2 D 3 in various clcitriol, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation rheumatoid arthritis, psoriatic arthritisdermatological indications psoriasis, actinic keratosis, seborrheic dermatitis, photoagingosteoporosis postmenopausal and steroid-induced osteoporosiscancers prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinomasecondary hyperparathyroidism, and autoimmune diseases systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation.
As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, caocitriol results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma.
This review calcittriol with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
VDR and its functional unit. However, the observation that VDR is also present in cells other than those of the intestine, bone, kidney, and parathyroid gland led to the recognition of noncalcemic actions of VDR ligands. As a result, VDR is also known to be involved in cell proliferation, differentiation, and immunomodulation. This activation or disease-specific up-regulation of VDR protein provides an opportunity to treat these conditions with VDR ligands.
The expression of VDR in a variety of cell lines and primary cells, coupled with the increased evidence regarding the involvement of VDR in the processes of cell differentiation, inhibition of proliferation, and immunoregulation, has prompted testing calcitrol the therapeutic effect of VDR ligands in several human diseases Table 1 as well as in buls animal models bua diseases. These efforts have led to the development of VDR ligands for bulx treatment of psoriasis 2 — 4secondary hyperparathyroidism 5and osteoporosis 67.
In addition, VDR ligands have bulaa some efficacy calcitrio, limited open clinical trials for prostate cancer, myelodysplasia a precancerous statepsoriatic arthritis, and RA. Examples of vitamin D analogs that have undergone clinical trials with positive outcome are shown in Table 1. VDR ligands have also shown efficacy in the prevention and treatment of inflammatory and autoimmune diseases in various animal models.
The goal of this article is to review calcitruol progress in the field of noncalcemic actions of vitamin D and its analogs with a particular emphasis on the current and potential therapeutic applications of VDR ligands. To calcutriol the references to a reasonable number, many recent up-to-date reviews are included, sometimes in place of relevant articles.
We apologize to our colleagues when, due to lack of space, a recent review article is mentioned instead of the multiple original references.
Structures, common names, and chemical names of vitamin D analogs are presented. In the absence of calcitgiol and serum in cellular systems, most of the VDR is present in the cytoplasm 9. However, noncanonical VDREs, such as an everted repeat of this hexanucleotide motif with a spacer of 6 bp ER-6 motif has been described in the promoter region of human Cyp3A4 gene The Calcittriol protein is modular in nature and like other nuclear receptors can be functionally divided into three regions with well-characterized functions.
The NH 2 -terminal region contains a ligand-independent transactivation function, activation function-1 AF The C-terminal region of the receptor contains a multifunctional domain harboring the ligand binding domain LBDthe RXR heterodimerization motif, and a ligand-dependent transactivation function, AF Unlike other nuclear receptors, there is only one isoform encoded by cqlcitriol single gene in humans and other organisms.
Most of the variant transcripts produce the same classical VDR protein of amino acids VDR is a ligand-dependent transcription factor that can modulate the expression of vitamin D-responsive genes in three different ways Fig. Genes that are down-regulated in response to 1, OH 2 D 3 and its synthetic analogs are also listed in Fig. The known hyperproliferative and inflammatory functions of these gene products indicate that many of the therapeutic effects of 1, OH 2 D 3 and its analogs could result from their negative gene regulatory or transrepression activities.
Proliferation-associated genes that are repressed by VDR ligands include epidermal growth factor receptor EGF-R keratinocytes 37c-myc keratinocytes 37and K16 psoriatic plaques Regulation of gene expression by VDR ligands.
Noncalcemic Actions of Vitamin D Receptor Ligands | Endocrine Reviews | Oxford Academic
A schematic representation of VDR-mediated regulation of gene expression is presented. References are given in parentheses. Using genetic and biochemical approaches, a number of cofactors that interact with VDR and other nuclear receptors in a ligand-dependent manner have been identified. VDR-interacting cofactors are listed in Table 2. Cofactor proteins do not show any DNA binding activity but possess the capability to modulate gene expression in transfected systems. Cofactors include two functionally distinct families of proteins, namely coactivators and corepressors.
Coactivators mediate induction of transcription, whereas the reciprocal family of corepressors binds to the unliganded or antagonist-occupied nuclear receptors and suppresses the expression of responsive genes. Sug1 has also been found to have DNA helicase activity The first step involves the recruitment of VDR-SRC or a VDR-histone acetyltransferase activity complex to a responsive promoter to facilitate the destabilization of the nucleosomal core.
This two-step model is currently in vogue but may get more complex as additional DRIPs are discovered. These corepressors recruit histone deacetylase activities that deacetylate the lysine residues present in the N-terminally located histone tails, resulting in chromatin compaction and silencing of genes. Ligand binding induces a receptor conformation that creates a hydrophobic cleft, thus rendering the nuclear receptor receptive to interaction with coactivators through their NR boxes LXXLL motifs.
The number of VDR-interacting cofactors indicates that even combinatorial and parallel receptor-interacting complexes may exist. Understandably, with the discovery of a plethora of receptor-interacting proteins, the transcription picture has become more complicated.
But this scenario also provides an opportunity of increased understanding of tissue- and gene-selective transcription by natural and synthetic ligands. Although structures for many nuclear receptors with or without ligands were available, obtaining a good model for 1, OH 2 D 3 complexed VDR was challenging. The VDR LBD has an insertion domain from amino acid residues — that is poorly conserved between different species, with no obvious biological significance Members of the nuclear receptor superfamily exhibit not only the same modular domain structure but also a moderately conserved LBD The relative position of N-terminal helix H1 is conserved among all nuclear receptors, and it provides intramolecular contacts for the stabilization of the global structure of LBD.
In VDR, helices H1 and H3 are connected by two short helices, H2 and H3n, where H3n is predicted by secondary structure predictions in the place of a loop structure that is present in other nuclear receptors Positioning of the ligand in the ligand-binding cavity is clearly shown by making helices H3 and H2 translucent. The 1, OH 2 D 3 is represented as ball and stick embedded in translucent surface in pink color. Few of the residues close to the ligand are displayed in stick model identified with one letter amino acid code and the residue number in blue.
The helix-7 H7 is directly behind the ligand in this orientation and thus is not visible. However, its location can be seen in panel A, which is represented as cylinders. These figures were produced using the published crystal structure coordinates A total of backbone atoms were used for superposition, and the RMS deviation was 1. The structure of the liganded VDR LBD 60 gives an opportunity to understand possible interactions between the natural ligand and the receptor.
Trp that is specific to VDR plays the crucial role of positioning the ligand. Trp forms an intramolecular hydrogen bond network with Ser, which in turn is hydrogen bonded to Met The ligand binding pocket is primarily composed of hydrophobic residues. The ligand curves around the helix H3, with its A ring interacting with the C terminus of helix H5 and the hydroxyl end close to helices H7 and H11 Figs.
The 1-hydroxyl forms two hydrogen bonds with Ser H3 and Arg H5whereas the 3-hydroxyl forms two hydrogen bonds with Ser H5 and Tyr Fig.
A water channel is also observed, with water molecules hydrogen bonded to Arg leading to the solvent Fig. The conjugated diene connecting the A and C rings nicely fits against the hydrophobic planar Trp stabilized by planar interactions.
The aliphatic chain adopts an extended conformation and is surrounded by hydrophobic residues. The hydroxyl group is hydrogen bonded to His which lies in the loop connecting H6 and H7 and His which lies in helix H11 Fig.
It is also observed that the His would be a hydrogen bond acceptor, whereas His would be a donor, given the network of hydrogen bonds around this region The interactions between amino acid residues lining the VDR ligand binding pocket and 1, OH 2 D 3 are schematically depicted herein. Residues that make potential hydrogen bonds to 1, OH 2 D 3 are shown in ball-and-stick. Ligand bonds are violetand bonds in the protein are reddish-yellow.
Oxygen atoms, except in water molecules, are filled in rednitrogen atoms in blueand carbons in black. The water molecules HOH are shown in cyan. Red spikes denote the hydrophobic interactions between the ligand atoms and the protein residues.
Hydrophobic contacts are discerned when the spikes from a ligand atom radiate out toward the protein residue which is represented as arcsand the spikes from that protein residue radiate out toward the same ligand atom.
In other words, the red spikes from a ligand atom and a protein residue facing each other are indicative of the hydrophobic interaction between the two.
The positioning of the helix H12 that is crucial for the coactivator binding and transactivation represents the agonist position in the published structure. This makes two direct Van der Waals contacts Val and Phe with the methyl groups of the ligand, thus indicating the modulation of helix H12 conformation and positioning by the ligand The position of helix H12 is also stabilized by a number of hydrophobic contacts and polar interactions Val, Ile, His, and Tyr The helix H12 residue Glu that makes a salt bridge with Lys of helix H4 has been implicated in ligand-dependent transactivation Recently, computer docking of a VDR ligand specific for the nongenomic actions has resulted in the identification of an alternative ligand binding pocket A-pocket that partially overlaps the 1, OH 2 D 3 -binding pocket G-pocket identified in the VDR-LBD crystal structure The elucidation of the crystal structure provides an opportunity for medicinal chemists to design and synthesize novel, nonsecosteroidal, high-affinity VDR ligands for the treatment of responsive indications.
Gene knockout studies in mice and VDR mutations in humans have provided considerable insights into the physiological functions of vitamin D. Four groups have created VDR knockout animals 67 — Female null mutant mice also displayed uterine hypoplasia and impaired folliculogenesis.
These mice died between 4 and 6 months of age. Interestingly, feeding animals with a diet rich in calcium, phosphate, and lactose normalized all the symptoms in null mice, except for hair abnormalities. These observations suggest that increased intestinal calcium absorption is critical for 1, OH 2 D 3 action on bone and calcium homeostasis.
Vitamin D-deficient animals have also been shown to develop hypocalcemia, rickets, and hyperparathyroidism, but unlike vitamin D-dependent rickets type II patients, never developed alopecia.
Thus, intact VDR is required for maintaining bone mineral homeostasis after birth as well as for normal hair development and hair follicle homeostasis. These studies also indicated that the defect lies in keratinocytes. In accordance with this notion, targeted expression of human VDR transgene to keratinocytes of VDR null mice prevented alopecia It is tempting to hypothesize that VDR-Hr interaction may modulate hair cycling by controlling the expression of an inhibitor of hair cycle.
Because RXR is the heterodimer partner of other nuclear receptors RAR, peroxisome proliferator activated receptor, liver X receptor, and thyroid hormone receptor resident in skin, these results suggest that only the RXR-VDR signaling pathway is involved in hair cycling.
VDR knockout mice were also found to have impaired insulin secretory capacity The growth plate development in compound knockout animals was more severely impaired in comparison to VDR null animals.
These findings indicate that both vitamin A and vitamin D signaling pathways are required for the normal development of growth plate chondrocytes. In addition to its central role in calcium and bone metabolism, 1, OH 2 D 3 has potent immunomodulatory effects on many immune cell types, including both innate and adaptive immune cells 79 — MS is a chronic inflammatory autoimmune disease of the central nervous system CNS in which self-epitopes on myelinated nerve fibers are inappropriately recognized by adaptive immune cells of the host.