The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)(2)D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1alpha-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1alpha-hydroxylase indicates both 1,25(OH)(2)D(3)-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)(2)D(3). Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1alpha-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)(2)D(3) in the control of cell proliferation and differentiation. This local production of 1,25(OH)(2)D(3) is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.

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The vitamin D endocrine systems plays a critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1,25-dihydroxyvitamin D3[1,25(OH)2D3], binds with high affinity to a specific cellular receptor that acts as a ligand-activated transcription factor. The activated vitamin D receptor (VDR) dimerizes with another nuclear receptor, the retinoid X receptor (RXR), and the heterodimer binds to specific DNA motifs (vitamin D response elements, VDREs) in the promoter region of target genes. This heterodimer recruits nuclear coactivators and components of the transcriptional preinitiation complex to alter the rate of gene transcription. 1,25(OH)2D3also binds to a cell-surface receptor that mediates the activation of second messenger pathways, some of which may modulate the activity of the VDR. Recent studies with VDR-ablated mice confirm that the most critical role of 1,25(OH)2D3is the activation of genes that control intestinal calcium transport. However, 1,25(OH)2D3can control the expression of many genes involved in a plethora of biological actions. Many of these nonclassic responses have suggested a number of therapeutic applications for 1,25(OH)2D3and its analogs.

the serum calcium was increased by the oral administration of calcium carbonate, the decrement in serum i-PTH was only 25±6.65% when compared with 73.5±5.08% (P < 0.001) obtained by the administration of intravenous 1,25(OH)2D3. Thus, a similar serum calcium achieved by intravenous 1,25(OH)2D3 rather than calcium carbonate has a greater suppressive effect in the release of PTH.These studies indicate that 1,25(OH)2D3 administered intravenously rather than orally may result in a greater delivery of the vitamin D metabolite to peripheral target tissues other than the intestine and allow a greater expression of biological effects of 1,25(OH)2D3 in peripheral tissues. The use of intravenous 1,25(OH)2D3 thus provides a simple and extremely effective way to suppress secondary hyperparathyroidism in dialysis patients.

total intracellular PTH was the non-PTH (1-84), most likely A novel mechanism for skeletal resistance in uremia.PTH 7-84. Background. In treating secondary hyperparathyroidism, Conclusion. In patients with chronic renal failure, the presthe target level of serum intact parathyroid hormone (I-PTH) ence of high circulating levels of non-1-84 PTH fragments should be three to five times normal to prevent adynamic bone (most likely 7-84 PTH) detected by the "intact" assay and the disease. In circulation, there is a non-(1-84) PTH-truncated antagonistic effects of 7-84 PTH on the biological activity of fragment, likely 7-84, which, in addition to PTH 1-84, is mea-1-84 PTH explain the need of higher levels of "intact" PTH sured by most I-PTH immunoradiometric (IRMA) assays, givto prevent adynamic bone disease. ing erroneously high I-PTH values. We have developed a new IRMA assay in which the labeled antibody recognizes only the first six amino acids of the PTH molecule. Thus, this new IRMA assay (Whole PTH) measures only the biologically active 1-84 Parathyroid hormone (PTH), a single-chain polypep-PTH molecule. tide of 84 amino acids [1], plays a critical role in the Methods. Using this new IRMA assay (Whole PTH) and the Nichols "intact" PTH assay, we compared the ability of regulation of mineral metabolism. Ionized calcium, caleach assay to recognize human PTH (hPTH) 1-84 and hPTH citriol, and phosphorus are the three major regulators 7-84 and examined the percentage of non-1-84 PTH in circulaof PTH homeostasis in humans. tion and in parathyroid glands. Possible antagonistic effects of The human PTH gene is located on the short arm of the 7-84 PTH fragment on the biological activity of 1-84 PTH chromosome 11. The coding region spans more than 4 in rats were also tested. Results. In 28 uremic patients, PTH values measured with kb and consists of three exons. The first exon contains the Nichols assay, representing a combined measurement of the 5Ј untranslated region of the PTH transcript. Theboth hPTH 1-84 and hPTH 7-84, were 34% higher than with coding sequence spans exons 2 and 3. The spliced cytothe Whole assay (hPTH 1-84 only); the median PTH was 523 plasmic transcript is 772 bases long. The primary translaversus 318 pg/mL (P Ͻ 0.001). Similar results were found in tion product, pre-pro-PTH (115 amino acids), is formed 14 renal transplant patients. In osteoblast-like cells, ROS 17.2, 1-84 PTH (10 Ϫ8 mol/L) increased cAMP from 18.1 Ϯ 1.25 to in the rough endoplasmic reticulum of parathyroid chief 738 Ϯ 4.13 mmol/well. Conversely, the same concentration of cells [2] and is converted within seconds to pro-PTH (90 7-84 PTH had no effect. In parathyroidectomized rats fed a amino acids) [3]. In the Golgi apparatus, pro-PTH is calcium-deficient diet, 7-84 PTH was not only biologically inacconverted to intact PTH (I-PTH; 84 amino acids) approxtive, but had antagonistic effects on 1-84 PTH in bone. Plasma calcium was increased (0.65 mg/dL) two hours after 1-84 PTH imately 15 minutes after the biosynthesis of the original tre...