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We identified and characterized a novel rat vitamin D receptor isoform (rVDR1), which retains intron 8 of the canonical VDR (rVDR0) during alternative splicing. In this isoform protein directed by the stop codon in this newly identified exon, a part of the ligand binding domain (86 amino acids) is truncated at the C-terminal end but contains 19 extra amino acids. The rVDR1 transcript was expressed at a level 1/15 to 1/20 of that of rVDR0 in the kidney and intestine in adult rats but not in embryos. The recombinant rVDR1 protein showed no ligand binding activity. Homo-and heterodimers of the recombinant rVDR0 and rVDR1 proteins bound to a consensus vitamin D response element (VDRE) but not to consensus response elements for thyroid hormone and retinoic acid. However, unlike rVDR0, rVDR1 did not form a heterodimeric complex with RXR on the VDRE. A transient expression assay showed that this isoform acted as a dominant negative receptor against rVDR0 transactivation. Interestingly, the dominant negative activities of rVDR1 differed among VDREs. Thus, the present study indicates that this new VDR isoform negatively modulates the vitamin D signaling pathway, through a particular set of target genes.Most of the biological actions of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], such as regulating calcium homeostasis and cytodifferentiation, are exerted through gene expression mediated by the nuclear vitamin D receptor (VDR) (for a review, see reference 8). VDR is a member of the nuclear receptor superfamily, which functions as a ligand-inducible transcription factor (for reviews, see references 2, 10, 13, and 39). This family includes nuclear receptors for steroid hormones, thyroid hormone, retinoic acid, and unknown ligands (orphan receptors). Together with the retinoid receptors (RAR␣, -, and -␥ and RXR␣, -, and -␥) and thyroid hormone receptors (TR ␣ and ), VDR forms a subfamily, based on structural and functional similarities, in the nuclear receptor superfamily. Like RARs and TRs, VDR heterodimerizes with RXR. These heterodimers bind distinct but similar target enhancer elements composed of two directly repeated core AGGTCA (or related hexamer core) motifs. The spacer between the two core motifs (3 bp [DR3] for RXR/VDR, 4 bp [DR4] for RXR/TR, and 2 [DR2] and [DR5] 5 bp for RXR/RAR) discriminates among these nuclear receptors for recognizing target enhancer elements (for reviews, see references 12, 19, 22, 41, and 50). In addition to the heterodimeric form of VDR with RXR, VDR forms a homodimer with some vitamin D response elements (VDRE), suggesting the presence of two signaling pathways for vitamin D (5, 48). Irrespective of the functional and structural similarities of these receptors, only one type of VDR protein has been found in sharp contrast to multiple subtypes and isoforms of RAR, RXR, and TR (17, 24, 53). The RAR and TR isoforms are generated by alternative splicing and/or by direction of differential promoters. Functional analysis by a transient-expression assay showed that the transactivational acti...
Context: Osteoporosis is a metabolic bone disease. The effect of blood metabolites on the development of osteoporosis remains elusive.Objective: To explore the relationship between blood metabolites and osteoporosis.Design and Methods: We used 2286 unrelated white subjects for the discovery samples and 3143 unrelated white subjects from the Framingham Heart Study (FHS) for the replication samples. The bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using Affymetrix Human SNP Array 6.0 (for discovery samples) and Affymetrix SNP 500K and 50K array (for FHS replication samples). The SNP sets significantly associated with blood metabolites were obtained from a reported whole-genome sequencing study. For each subject, the genetic risk score of the metabolite was calculated from the genotype data of the metabolite-associated SNP sets. Pearson correlation analysis was conducted to evaluate the potential effect of blood metabolites on the variations in bone phenotypes; 10,000 permutations were conducted to calculate the empirical P value and false discovery rate.Results: We analyzed 481 blood metabolites. We identified multiple blood metabolites associated with hip BMD, such as 1,5-anhydroglucitol (P discovery , 0.0001; P replication = 0.0361), inosine (P discovery = 0.0018; P replication = 0.0256), theophylline (P discovery = 0.0048; P replication = 0.0433, gamma-glutamyl methionine (P discovery = 0.0047; P replication = 0.0471), 1-linoleoyl-2-arachidonoyl-GPC (18:2/20:4n6; P discovery = 0.0018; P replication = 0.0390), and X-12127 (P discovery = 0.0002; P replication = 0.0249). Conclusions:Our results suggest a modest effect of blood metabolites on the variations of BMD and identified several candidate blood metabolites for osteoporosis. (J Clin Endocrinol Metab 103: 1850-1855 O steoporosis is a metabolic bone disease, characterized as low bone mass and increased bone fragility. It has been reported that currently .40 million people are at risk of bone fractures, and the incidence of osteoporotic fractures is increasing rapidly in the United States (1). Bone mineral density (BMD) is commonly used to 1850https://academic.oup.com/jcem
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