Ligand binding, involving the AF2 domain, imparts a conforma- tional change in the secondary structure of the VDR which triggers the recruitment of motor proteins responsible for cytoplasmic VDR transition to the nucleus along microtubules. VDR heterodimerization with its protein partner RXR confers a conformational structure to the receptor which is critical for transactivation function by high affinity interaction with VDREs in the promoter region of vitamin D-responsive genes (Figure 3). During VDR-RXR interaction with the most common VDRE type, DR3, RXR binds the 5′ half-site and the VDR occupies the 3′ one. According to mutagenesis experiments in the VDRE of avian parathyroid hormone (PTH) gene promoter, the switch between VDR-RXR-activated or -repressed gene transcription depends on the polarity of the VDR/RXR-VDRE complex. However recent experimental evidences regarding VDR interactions with nuclear coregulator molecules and their action on VDR-mediated regulation of gene transcription have provided further complexity to the entire mechanism. In fact RXR heterodimerization and AF2 domains are both involved in interactions with nuclear proteins which serves as VDR-coregulators (36). In details the ligand-induced conformational change in AF2 domain is critical for the receptor to interact with components of the transcription initiation complex, RNA polymerase II and nuclear transcription coactivators which promote chromatin remodelling necessary to gene transcription. Some of them in fact, such as SRC-1 and CBP/p300 are histone acetylases which determines the recruitment of a second complement of transcription coactivators, the DRIP- TRAP complex. This is a 15 proteins-complex which facilitates the assembly of the preinitiation complex thus strengthening VDR-induced gene transcription. Binding of VDR-RXR complex to a negative VDRE promotes recruitment of corepressors which have histone deacetylase activity and then inhibit binding of proteins promoting the assembly of the transcription machinery. The situation is further complicated by comod- ulator proteins, such as NCoA62/Skip which can act as core- pressor or coactivator depending on the specific cell context of coregulator molecules. The NH2-terminal region of Skip protein is targeted by both nuclear corepressors, such as NCoR, and coactivators, like CBP/p300, and more importantly some of them are under VDR-mediated transcriptional regulation. Recently an ATP-dependent chromatin remodelling complex has been demonstrated to amplify VDR activation and repression of transcription.
The vitamin D receptor: biological and molecular properties. Transcriptional regulation by VDR
The vitamin D receptor: biological and molecular properties

Introduction
Vitamin D receptor (VDR) is the responsible of much of the vitamin D [1,25-(OH)2D3] signalling. It is a direct regulator of gene transcription, belonging to the nuclear receptor family. Within this family, it has sequence and structure resemblance with the subfamily that includes retinoic acid, thyroid hormone and peroxisome proliferator activator receptor (PPAR) receptors. VDR is a protein of 427 amino acids, with a molecular mass of approximately 48 kDa. Similarly to the other nuclear receptors VDR consists of several distinct functional domains, namely the NH2 terminus A/B domain whose function is still unclear, a DNA binding domain (DBD), termed C domain, spanning from amino acid 20 to 90, a hinge or D domain (amino acids 90 to 130) and the ligand binding domain (LBD), or E domain, spanning from amino acid 130 to 423. The last one is the most complex domain of the protein as it is responsible for the specific binding of VDR ligands, for heterodimerization with retinoid X receptor (RXR) and for interactions with transcription factors (Figure 1).
VDR cDNA was firstly cloned from chicken and shortly thereafter from human. Genomic organization of the human VDR gene, which locates on chromosome 12q13-14, is similar to other nuclear receptor genes. The gene is made up of 11 ex- ons spanning approximately 75 kb (Figure 2). The non coding 5′ end of the gene includes several exon 1 isoforms (from 1A to 1E) while exons 2-9 encode the structural portion of the VDR gene product. Alternative splicing of exon 1 provides at least five different VDR mRNA transcripts, while the presence of a polymorphic sequence in exon 2 determines the presence or absence of an alternative start translation site. Most of the promoter sequence is upstream exon 1 and has high GC content but does not contain an apparent TATA box. The promoter is capable to generate multiple tissue-specific transcripts and is positioned just downstream from collagen type II alpha 1 gene. A unique feature for this gene is the presence of an additional exon that is not found in other nuclear hormone receptors family members. It encodes for an insertion peptide of about 40 amino acid that locates in the LBD of the receptor. VDR binds its physiological ligand 1,25-(OH)2D3 with high affinity (about 10-10 M) and both hydroxyl groups seem to be relevant in determining it as the absence of either results in approximately a 500-fold decrease in affinity. Although widely expressed, VDR protein levels are usually low and reach relatively high values only in targets tissues such as bone, kidney and intestine (3,000-6,000 fmol/mg protein). In contrast to other nuclear receptors which are usually bound to cytoplasmic proteins before hormone binding, VDR is predominantly nuclear.
Osteoporosis in men: a study in patients affected by chronic non-advanced liver disease. Discussion

Recently the medical community got to acknowledge that, although not as relevant as in women, male osteoporosis is an epidemiologically relevant feature of the disease and one out of three osteoporosis fractures occurs in the male population. Aim of this study was to evaluate bone mineral density and bone metabolism markers in a selected series of male patients affected only by viral, non-advanced chronic liver disease. This illness is known to affect patients metabolism, possibly leading to hypermetabolism affecting also the bone turnover. The eccessive bone turnover activity can lead to an alteration of bone trabeculae, and to their perforation. This fact leads to a damage of bone micro-architecture and, consequently, to the reduction of proper mechanical characteristics of the bone segment and to increased risk of fracture. The present study shows that viral chronic liver disease in man is associated with reduced bone mineral density. In fact BMD at LS was significantly lower in liver patients as compared to controls (p<0.05) and BMD at FN showed a trend to reduction even though the difference between patients and controls was not statistically significant (Table I). Data are obtained using two different groups of controls: 1) age, BMI-matched healthy volunteers, 2) population-based reference values. Osteoporosis has been described in patiens treated with orthotopic liver transplantation, as well as in subjects affected by advanced liver cirrhosis, primary biliary cirrhosis, cholestatic or alcoholic liver diseases, hemochromatosis and in corticosteroid treated patients, but little is known about bone mineral density in viral non advanced liver disease. A recent paper on this issue reported in viral cirrhosis in men a high prevalence of osteoporosis suggesting that it is a major cause of reduced bone mineral density in men. However, in this study three heterogeneous groups of patients, aged 3874, affected by different severity of liver disease, according to Child’s classification and Pugh’s score were studied: a significant correlation between BMD at lumbar spine and severity of liver disease was found. An advanced age and a more severe liver disease could both affect the results, therefore, in the present study we examined 25 male patients selected on the basis of very restricted criteria: it was a homogeneous group, without confounding factor affecting bone metabolism, B and C Child’s classes of liver cirrhosis and subsets aged > 60 years were excluded.
Osteoporosis in men: a study in patients affected by chronic non-advanced liver disease. Results
Clinical and laboratory data of patients and controls are reported in Table I.
BMD was reduced in 16 (64%) out of 25 patients: 5 patients (20%) could be classified as osteoporotic and 11 patients (44%) osteopenic on the basis of at least one measurement. Table II reports mean BMD values for lumbar spine (LS) and femoral neck (FN) in patients and controls, showing a decreased BMD in patients in both sides of measurements even if only for the LS it reaches the significance. In order to compare the BMD of our patients with reference population data we calculated the 95% CI of the mean Z-score at the LS and at the FN. Data showed that the mean Z-score at LS but not at FN among liver patients was significantly lower as compared to the age- and sex-matched general population (lumbar spine mean Z-score 95% CI = -1.06 to -0.920; femoral neck mean Z-score 95% CI = -0.54 to + 0.53). Using multiple linear regression analysis we investigated the relationship between BMD (gr/cm2) and the variables considered, including the time of detection of abnormal tests of liver function. No correlation was found between BMD and the variables studied.
Osteoporosis in men: a study in patients affected by chronic non-advanced liver disease. Patients and methods
In a one year period we studied 98 liver patients consecutively admitted to the III Department of Internal Medicine, Federico II University, Naples, Italy. Among them we selected 25 patients affected by biopsy-proven chronic hepatitis or liver cirrhosis, virus-related, according to the following inclusion criteria: male sex, age < 60 years, body mass index (BMI) from 20 to 30 kg/m2, normal physical activity, biopsy-proven liver cirrhosis only in Child’s A class, virus-related.
All patients lived in the same geographical area from Southern Italy. Their diet was a tipical mixed, mediterranean diet, containing milk and cheese products, without alcohol intake; only five patients consumed less than 20 g of alcohol three or four times a week. Information about dietary habits and alcohol intake were carefully obtained from a food frequency questionnaire.
Exclusion criteria were: female sex, age > 60 years, alcohol abuse, drug addiction, obesity, previous bone fractures or history of recent immobilization, autoimmune, endocrinological or rheumatological diseases, treatment with corticosteroids, diuretics, drugs affecting bone metabolism or interferon for more than three months over the past three years. Advanced liver cirrhosis (B or C Child’s class), hepatocellular carcinoma, primary biliary cirrhosis, cholestatic liver diseases, genetic he- mochromatosis were also considered exclusion criteria. The selected patients had positive serological markers for viral hepatitis (2 for hepatitis B virus and 23 for hepatitis C virus) and biopsy-proven diagnosis of chronic liver disease: 12 patients were affected by chronic hepatitis and 13 patients by liver cirrhosis, A Child’s class. Liver function was well preserved and renal function was normal in all patients. None exhibited indices of cholestasis nor experienced previous decompensation of cirrhosis.
Thirthy healthy male volunteers, living in the same geographical area, age, and BMI-matched, were also examined as control group.
Osteoporosis in men: a study in patients affected by chronic non-advanced liver disease

Introduction
Metabolic bone disease is a complication of chronic liver disease (CLD) and is well known as “hepatic osteodistrophy”. Osteoporosis accounts for the majority of cases, whereas osteomalacia is rare in the absence of advanced liver disease and severe malabsorption. The prevalence is the same in men and women, however the published prevalence of osteoporosis considerably differs and ranges from 20% to 100%, depending on patients selection and different diagnostic criteria. Many reports are referred to a broad spectrum of liver disease of different aetiology and severity: in patients with advanced liver disease candidates for or treated with orthotopic liver transplantation, osteoporosis is prevalent and contributes to a major source of morbidity preceding and following transplantation. Nevertheless, little is known about the prevalence among patients with non-advanced liver disease. The aetiology and pathogenesis of osteoporosis in these patients also remain undefined, even though its histology is quite similar to post-menopausal and age-related bone loss, affecting trabecular bone more rapidly than cortical bone. Finally, there is controversy about risk factors for osteoporosis in CLD: liver cirrhosis, cholestasis, hypogonadism, corticosteroid or immuno- suppressive treatment, alcohol consumption, malnutrition and malabsorption, sex, physical activity, subnormal vitamin D levels and/or vitamin D receptor genotype, insulin growth factor 1 (IGF-1) deficiency, as well as country and nationality are all reported factors affecting bone metabolism. However, whether non-advanced liver disease “per se” could be a risk factor for osteoporosis still remains uncertain; moreover there are few reports about the effects of viral liver disease on bone turnover.
Bone metabolism: Kidney
The presence of renal calcium leak is the basis for the so- called renal hypercalciuria, which is characterized by increased urine calcium, a tendency toward hypocalcemia, and a secondary increase in parathyroid hormone secretion. The latter is considered the main cause of bone loss in these patients. However, the large revision of the pathogenetic aspects of patients with PH led to the observation that less than 5% of hy- percalciuric patients suffer from a renal form of PH. As a consequence, the importance of renal calcium leak as a patho- genetic factor for bone loss in these patients was completely reconsidered. Discount drugs online cad-pharmacy.com
However, some other aspects seem to link the kidney to the complex relationships occurring between hypercalciuria and bone. Increased urinary phosphate excretion was found in hy- percalciuric patients as compared to normal subjects, irrespective of the presence of a true form of absorptive hypercalciuria with renal calcium leak. It was suggested that an excessive excretion of phosphate may be present in the majority of patients with PH, then concurring to the development of the hy- percalciuric state in the whole population of PH patients. Similar findings were reported by Prie et al. in hypercalciuric stone formers. They observed that the distribution of renal phosphate threshold normalized for glomerular filtration rate (TmPi) was quite different between patients and controls, with hypercalciuric patients showing a decreased value of TmPi in approximately 20% of cases. No assessment of bone status was made in the two papers. However, it could be hypothesized that the alteration in phosphate metabolism seen in these patients may play a role also in the pathogenesis of bone damage in hypercalciuric patients. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a paradigm of this pathophysiology. This disease shares some clinical aspects with the disorder seen in the Npt2 knockout mice, carrying the deletion of the gene of kidney-specific Na-Pi cotransporter, in which a delay in bone mineralization is seen 21 days after birth. These bone alterations may resemble those observed in hyper- calciuric patients by histomorphometric studies, in which an alteration in bone mineralization process was reported. Accordingly, a mutation of NPT2 gene was found in nephrolithiasic patients with decreased bone density by Prie and coworkers. In conclusion, even if no clear evidence supports the hypothesis that renal phosphate leak may be at least in part responsible for bone disease in PH patients, this research field appears as one of the most promising to better elucidate the role of kidney in the pathogenesis of bone loss in PH.
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