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 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.

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.

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...

To determine whether mononuclear cell secretory products contribute to the changes in bone turnover that characterize the development of postmenopausal osteoporosis, we evaluated the effects of oophorectomy and subsequent estrogen replacement on the spontaneous secretion of interleukin 1 (IL-1) and tumor necrosis factor a (TNF-a) and on the phytohemagglutinin A-induced secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) from peripheral blood mononuclear cells. In 15 healthy premenopausal women who underwent oophorectomy, increases in GM-CSF activity were observed as early as 1 week after surgery, whereas elevations in IL-1 and TNF-a and in hydroxyproline/creatinine and calcium/creatinine ratios, two urinary indices of bone resorption, were detectable 2 weeks after the surgical procedure. Six of the oophorectomized women received no estrogen therapy after surgery and in these subjects hydroxyproline/creatinine and calcium/creatinine ratios plateaued 6 weeks postoperatively, and all three cytokines reached the highest levels 8 weeks after oophorectomy, when the study ended. In the remaining 9 women, who were started on estrogen replacement therapy 4 weeks after oophorectomy, decreases in the indices of bone resorption paralleled decreases in the secretion of the cytokines, with lower levels detected after 2 weeks of therapy. In the women who did not receive estrogen therapy, circulating osteocalcin, a marker of bone formation, increased beyond preoperative levels 8 weeks after oophorectomy, whereas in the estrogen-treated subjects osteocalcin remained unchanged in the entire study period. In 9 female controls who underwent simple hysterectomy, cytokine release and biochemical indices of bone turnover did not change after surgery. These data indicate that changes in estrogen status in vivo are associated with the secretion of mononuclear cell immune factors in vitro and suggest that alterations in the local production of bone-acting cytokines may underlie changes in bone turnover caused by surgically induced menopause and estrogen replacement.Postmenopausal osteoporosis, a common disorder characterized by a decreased bone mass and increased fracture risk (1), stems from an accelerated loss of bone that begins after natural or surgically induced menopause and progresses rapidly for 5 or 10 years thereafter (2, 3). That estrogen deficiency plays a major role in this condition is well supported by the higher prevalence of osteoporosis in women than in men (4), by the increase in the rate of bone mineral loss detectable by bone densitometry after artificial or natural menopause (5, 6), and by the protective effect of estrogen replacement with respect to both bone mass loss and fracture incidence (7,8). Although the bone-sparing effect of estrogen appears to be related to an inhibitory effect on bone resorption (9), the mechanism of the estrogen response remains unknown.The discovery of estrogen receptors in osteoblasts (10-12) and osteoclasts (13) suggests that a direct mechanism(s) may be in...

Weight-bearing exercise led to significant increases above baseline in bone mineral content which were maintained with continued training in older, postmenopausal women. With reduced weight-bearing exercise, bone mass reverted to baseline levels. Further studies are needed to determine the threshold exercise prescription that will produce significant increases in bone mass.

Dietary phosphorus (P) restriction is known to ameliorate secondary hyperparathyroidism in renal failure patients. In early renal failure, this effect may be mediated by an increase in 1,25-(OH) 2 D 3 , whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH) 2 D 3 and serum ionized calcium (ICa). In this study, we examined the effects of dietary P on serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats. Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for 2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in uremic rats fed the 0.2% P diet. In contrast, there were significant increases in serum PTH (130 Ϯ 25 vs. 35 Ϯ 3.5 pg/ml, P Ͻ 0.01), PTG weight (1.80 Ϯ 0.13 vs. 0.88 Ϯ 0.06 g/gram of body weight, P Ͻ 0.01), and PTG DNA (1.63 Ϯ 0.24 vs. 0.94 Ϯ 0.07 g DNA/gland, P Ͻ 0.01) in the uremic rats fed the 0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25-(OH) 2 D 3 were not altered over this range of dietary P, suggesting a direct effect of P on PTG function. We tested this possibility in organ cultures of rat PTGs. While PTH secretion was acutely (30 min) regulated by medium calcium, the effects of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium (1,706 Ϯ 215 vs. 1,033 Ϯ 209 pg/ g DNA, P Ͻ 0.02); the medium ICa was 1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but cycloheximide (10 g/ml) abolished the effect of P on PTH secretion. Thus, the effect of P is posttranscriptional, affecting PTH at a translational or posttranslational step. Collectively, these in vivo and in vitro results demonstrate a direct action of P on PTG function that is independent of ICa and 1,25-(OH) 2 D 3 . ( J. Clin. Invest. 1996. 97:2534-2540.)