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Skeletal unloading in an animal hindlimb suspension model and microgravity experienced by astronauts or as a result of prolonged bed rest causes site-specific losses in bone mineral density of 1%-2% per month. This is accompanied by reductions in circulating levels of 1,25-(OH)(2)D(3), the active metabolite of vitamin D. 1,25-(OH)(2)D(3), the ligand for the vitamin D receptor (VDR), is important for calcium absorption and plays a role in differentiation of osteoblasts and osteoclasts. To examine the responses of cells to activators of the VDR in a simulated microgravity environment, we used slow-turning lateral vessels (STLVs) in a rotating cell culture system. We found that, similar to cells grown in microgravity, MG-63 cells grown in the STLVs produce less osteocalcin, alkaline phosphatase, and collagen Ialpha1 mRNA and are less responsive to 1,25-(OH)(2)D(3). In addition, expression of VDR was reduced. Moreover, growth in the STLV caused activation of the stress-activated protein kinase pathway (SAPK), a kinase that inhibits VDR activity. In contrast, the 1,25-(OH)(2)D(3) analog, EB1089, was able to compensate for some of the STLV-associated responses by reducing SAPK activity, elevating VDR levels, and increasing expression of osteocalcin and alkaline phosphatase. These studies suggest that, not only does simulated microgravity reduce differentiation of MG-63 cells, but the activity of the VDR, an important regulator of bone metabolism, is reduced. Use of potent, less calcemic analogs of 1,25-(OH)(2)D(3) may aid in overcoming this defect. 相似文献
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J L Finch A S Dusso T Pavlopoulos E A Slatopolsky 《Journal of the American Society of Nephrology : JASN》2001,12(7):1468-1474
19-Nor-1,25-(OH)(2)D(2), an analog of 1,25-(OH)(2)D(3), is used to treat secondary hyperparathyroidism because it suppresses parathyroid hormone synthesis and secretion with lower calcemic and phosphatemic activities. 19-Nor-1,25-(OH)(2)D(2) is approximately 10 times less active than 1,25-(OH)(2)D(3) in promoting bone resorption, which accounts in part for the low potency of this analog in increasing serum calcium and phosphorus. Concern that 19-nor-1,25-(OH)(2)D(2) also could be less potent than 1,25-(OH)(2)D(3) on bone formation led to a comparison of the potency of both compounds on osteoblasts. In the human osteoblast-like cell line MG-63, 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) had a similar potency in upregulating vitamin D receptor content and suppressing proliferation. Both sterols caused a similar reduction in DNA content and proliferating cell nuclear antigen protein expression. Time-course and dose-response studies on 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) induction of the marker of bone formation, osteocalcin, showed overlapping curves. The effects on alkaline phosphatase (ALP) activity also were studied in MG-63 cells that had been co-treated with either sterol and transforming growth factor-beta, an enhancer of 1,25-(OH)(2)D(3)-induced ALP activity in this cell line. Transforming growth factor-beta alone had no effect, whereas 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) increased ALP activity similarly. These studies demonstrate that 19-nor-1,25-(OH)(2)D(2) has the same potency as 1,25-(OH)(2)D(3) not only in inducing vitamin D receptor content, osteocalcin levels, and ALP activity but also in controlling osteoblastic growth. Therefore, it is unlikely that 19-nor-1,25-(OH)(2)D(2) would have deleterious effects on bone remodeling. 相似文献
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Dusso AS 《Kidney international. Supplement》2003,(85):S6-S9
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Silver J 《Advances in renal replacement therapy》2002,9(3):159-167
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《BONE》2013,55(2):237-243
The active form of vitamin D [1,25(OH)2D] is an important regulator of calcium and bone homeostasis, as evidenced by the consequences of 1,25(OH)2D inactivity in man and mice, which include hypocalcemia, hypophosphatemia, secondary hyperparathyroidism and bone abnormalities. The recent generation of tissue-specific (intestine, osteoblast/osteocyte, chondrocyte) vitamin D receptor (Vdr) null mice has provided mechanistic insight in the cell-specific actions of 1,25(OH)2D and their contribution to the integrative physiology of VDR signaling that controls bone and mineral metabolism. These studies have demonstrated that even with normal dietary calcium intake, 1,25(OH)2D is crucial to maintain normal calcium and bone homeostasis and accomplishes this primarily through stimulation of intestinal calcium transport. When, moreover, insufficient calcium is acquired from the diet (severe dietary calcium restriction, lack of intestinal VDR activity), 1,25(OH)2D levels will increase and will directly act on osteoblasts and osteocytes to enhance bone resorption and to suppress bone matrix mineralization. Although this system is essential to maintain normal calcium levels in blood during a negative calcium balance, the consequences for bone are disastrous and generate an increased fracture risk. These findings evidently demonstrate that preservation of serum calcium levels has priority over skeletal integrity. Since vitamin D supplementation is an essential part of anti-osteoporotic therapy, mechanistic insight in vitamin D actions is required to define the optimal therapeutic regimen, taking into account the amount of dietary calcium supply, in order to maximize the targeted outcome and to avoid side-effects. We will review the current understanding concerning the functions of osteoblastic/osteocytic VDR signaling which not only include the regulation of bone metabolism, but also comprise the control of calcium and phosphate homeostasis via fibroblast growth factor (FGF) 23 secretion and the maintenance of the hematopoeitic stem cell (HSC) niche, with special focus on the experimental data obtained from systemic and osteoblast/osteocyte-specific Vdr null mice.This article is part of a Special Issue entitled "The Osteocyte". 相似文献
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1,25-Dihydroxy-19-nor-vitamin D(2), a vitamin D analog with reduced bone resorbing activity in vitro
Holliday LS Gluck SL Slatopolsky E Brown AJ 《Journal of the American Society of Nephrology : JASN》2000,11(10):1857-1864
1,25-Dihydroxy-19-nor-vitamin D(2) (19-norD(2)), a new analog of 1,25(OH)(2)D(3), suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)(2)D(3). Although 19-norD(2) has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)(2)D(3), it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD(2) on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD(2) and 1,25(OH)(2)D(3) (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD(2), as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)(2)D(3)-stimulated osteoclasts (P < 0. 05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD(2) in cultures was approximately 20% greater than 1, 25(OH)(2)D(3), not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD(2) and 1,25(OH)(2)D(3). In summary, 19-norD(2) is less effective than 1,25(OH)(2)D(3) in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD(2) compared with 1,25(OH)(2)D(3). 相似文献
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Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. 总被引:1,自引:0,他引:1
Mara J Horwitz Mary Beth Tedesco Susan M Sereika Mushtaq A Syed Adolfo Garcia-Oca?a Alessandro Bisello Bruce W Hollis Clifford J Rosen John J Wysolmerski Pamela Dann Caren Gundberg Andrew F Stewart 《Journal of bone and mineral research》2005,20(10):1792-1803
Osteoblast activity and plasma 1,25(OH)2 vitamin D are increased in HPT but suppressed in HHM. To model HPT and HHM, we directly compared multiday continuous infusions of PTH versus PTHrP in humans. Continuous infusion of both PTH and PTHrP results in marked and prolonged suppression of bone formation; renal 1,25(OH)2D synthesis was stimulated effectively by PTH but poorly by PTHrP. INTRODUCTION: PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism (HPT) and humoral hypercalcemia of malignancy (HHM), respectively. Whereas HHM and HPT resemble one another in many respects, osteoblastic bone formation and plasma 1,25(OH)2 vitamin D are increased in HPT but reduced in HHM. MATERIALS AND METHODS: We performed 2- to 4-day continuous infusions of escalating doses of PTH and PTHrP in 61 healthy young adults, comparing the effects on serum calcium and phosphorus, renal calcium and phosphorus handling, 1,25(OH)2 vitamin D, endogenous PTH(1-84) concentrations, and plasma IGF-1 and markers of bone turnover. RESULTS: PTH and PTHrP induced comparable effects on renal calcium and phosphorus handling, and both stimulated IGF-1 and bone resorption similarly. Surprisingly, PTH was consistently more calcemic, reflecting a selectively greater increase in renal 1,25(OH)2 vitamin D production by PTH. Equally surprisingly, continuous infusion of both peptides markedly, continuously, and equivalently suppressed bone formation. CONCLUSIONS: PTHrP and PTH produce markedly different effects on 1,25(OH)2 vitamin D homeostasis in humans, leading to different calcemic responses. Moreover, both peptides produce profound suppression of bone formation over multiple days, contrasting with events in HPT, but mimicking HHM. These findings underscore the facts that the mechanisms underlying the anabolic skeletal response to PTH and PTHrP in humans is poorly understood, as are the signal transduction mechanisms that link the renal PTH receptor to 1,25(OH)2 vitamin D synthesis. These studies emphasize that much remains to be learned regarding the normal regulation of vitamin D metabolism and bone formation in response to PTH and PTHrP in humans. 相似文献
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Brown AJ Finch J Takahashi F Slatopolsky E 《Journal of the American Society of Nephrology : JASN》2000,11(11):2088-2094
19-Nor-1,25(OH)(2)D(2) (19-norD(2)) has been shown to suppress parathyroid hormone effectively, but with lower calcemic activity than 1,25(OH)(2)D(3). The present study investigated potential mechanisms to explain the reduced calcemic response to 19-norD(2). Tissue localization of [(3)H]19-norD(2) or[(3)H]1,25(OH)(2)D(3) after a single injection was not different. Intestinal calcium absorption and bone mobilization, measured in vitamin D-deficient rats 24 h after single injections of 60 or 600 pmol of 19-norD(2) or 1,25(OH)(2)D(3), were enhanced to a similar degree by the two compounds. However, when normal rats were treated every other day with 240 pmol of 19-norD(2) or 1,25(OH)(2)D(3), increases in serum calcium were identical 24 h after the first injection but diverged thereafter with significantly lower serum calcium in the 19-norD(2)-treated rats by 5 d. Intestinal calcium absorption and bone calcium mobilization were reassessed in vitamin D-deficient rats after seven daily injections of 600 pmol of 19-norD(2) or 1, 25(OH)(2)D(3), and both parameters were significantly lower in the 19-norD(2)-treated rats. Pharmacokinetic analysis after seven daily injections of 600 pmol of 19-norD(2) or 1,25(OH)(2)D(3) showed similar localization to the intestine and bone. In addition, intestinal vitamin D receptor levels were not different after 1 wk of treatment with 19-norD(2) or 1,25(OH)(2)D(3). In conclusion, the low calcemic activity of 19-norD(2) seems to be due to an acquired, postreceptor resistance of the intestine and bone to chronic treatment with the analog. 相似文献
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Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. 总被引:1,自引:0,他引:1
Alexander J Karnauskas Johannes P T M van Leeuwen Gert-Jan C M van den Bemd Paru P Kathpalia Hector F DeLuca David A Bushinsky Murray J Favus 《Journal of bone and mineral research》2005,20(3):447-454
The functional status and mechanism of increased VDR in GHS rats were investigated. Basal VDR and calbindins were increased in GHS rats. 1,25(OH)(2)D(3) increased VDR and calbindins in controls but not GHS rats. VDR half-life was prolonged in GHS rats. This study supports the mechanism and functional status of elevated VDR in GHS rats. INTRODUCTION: Genetic hypercalciuric stone-forming (GHS) rats form calcium kidney stones from hypercalciuria arising from increased intestinal calcium absorption and bone resorption and decreased renal calcium reabsorption. Normal serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels and increased vitamin D receptor (VDR) protein suggest that high rates of expression of vitamin D-responsive genes may mediate the hypercalciuria. The mechanism of elevated VDR and state of receptor function are not known. MATERIALS AND METHODS: GHS and non-stone-forming control (NC) male rats (mean, 249 g), fed a normal calcium diet, were injected intraperitoneally with 1,25(OH)2D3 (30 ng/100 g BW) or vehicle 24 h before cycloheximide (6 mg/100 g, IP) and were killed 0-8 h afterward. Duodenal VDR was measured by ELISA and Western blot, and duodenal and kidney calbindins (9 and 28 kDa) were measured by Western blots. RESULTS AND CONCLUSIONS: Duodenal VDR protein by Western blot was increased 2-fold in GHS versus NC rats (633 +/- 62 versus 388 +/- 48 fmol/mg protein, n = 4, p < 0.02), and 1,25(OH)2D3 increased VDR and calbindins (9 and 28 kDa) further in NC but not GHS rats. Duodenal VDR half-life was prolonged in GHS rats (2.59 +/- 0.2 versus 1.81 +/- 0.2 h, p < 0.001). 1,25(OH)2D3 prolonged duodenal VDR half-life in NC rats to that of untreated GHS rats (2.59 +/- 0.2 versus 2.83 +/- 0.3 h, not significant). This study supports the hypothesis that prolongation of VDR half-life increases VDR tissue levels and mediates increased VDR-regulated genes that result in hypercalciuria through actions on vitamin D-regulated calcium transport in intestine, bone, and kidney. 相似文献
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J Meyer C S Fullmer R H Wasserman B S Komm M R Haussler 《Journal of bone and mineral research》1992,7(4):441-448
We investigated the regulation of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-induced calbindin-D28k (CaBP) and of the vitamin D receptor (VDR) by evaluating CaBP protein, CaBP mRNA, and VDR mRNA under conditions of altered intake of vitamin D, calcium, or phosphorus. Chickens were maintained for 10 days on one of four diets: vitamin D-deficient, normal (1.0% Ca and 1.1% P), low calcium (0.1% Ca and 1.2% P), and low phosphorus (1.1% Ca and 0.3% P). CaBP was undetectable in D-deficient duodena and was elevated above normal values by low-calcium (3.1-fold) and low-phosphorus (2.3-fold) intake. Contradictory to published data, we observed a correlation between CaBP protein and mRNA levels in that the CaBP mRNA was absent in D-deficient intestine and augmented threefold and twofold in low-calcium and low-phosphate duodena, respectively. In contrast, VDR mRNA concentrations were identical in vitamin D-deficient and normal duodena, implying that intestinal VDR is not dependent upon 1,25-(OH)2D3 for basal expression. Chickens fed a low-phosphorus diet displayed a twofold increase in VDR mRNA, but those fed a low-calcium diet exhibited a dramatic decrease in VDR mRNA. These data show that CaBP mRNA and protein levels are modulated in a tightly coupled fashion, and they are consistent with previous conclusions that augmented circulating 1,25-(OH)2D3 stimulates CaBP expression when dietary calcium or phosphorus is limiting. However, a more complex regulation of VDR expression occurs in that low-phosphorus restriction enhances VDR mRNA levels, possibly via increased circulating 1,25-(OH)2D3. Conversely, reduced dietary calcium diminishes VDR mRNA despite increased circulating 1,25-(OH)2D3, indicating that another factor, such as parathyroid hormone, is a predominant downregulator of VDR. 相似文献
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Renal osteodystrophy is the term used to describe the spectrum of bone diseases associated with chronic renal failure. Deficiency of 1,25-dihydroxycholecalciferol (calcitriol) plays a major role in the development of renal osteodystrophy, in particular the evolution of secondary hyperparathyroidism. In recent decades, our understanding of the complex interactions between calcium, phosphorus, vitamin D, and parathyroid hormone (PTH) has increased, resulting in a rational approach to therapy in which vitamin D analogs have become an essential component. The initial vitamin D analogs that have been in widespread clinical use include calcitriol (1,25-[OH](2)D(3)) and alfacalcidol (1alpha-[OH]D(3)). These agents have been extensively studied to optimize their effects on secondary hyperparathyroidism. The occurrence of significant hypercalcemia and hyperphosphatemia limiting their use has led to the development of alternative vitamin D analogs that effectively reduce PTH secretion without causing these complications. Recently, 3 such analogs, 22-oxa-1,25-(OH)(2)D(3) (OCT), 1alpha-(OH)D(2) (doxercalciferol), and 19-nor-1,25-(OH)(2)D(2) (paricalcitol), have been released for clinical use. Only paricalcitol has been studied in comparative human clinical trials with calcitriol in dialysis patients. Preliminary findings suggest a clinical advantage over calcitriol, however, analysis of the larger comparative studies are forthcoming. 相似文献
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The aim of this study was to clarify the difference in the effects of vitamin K and vitamin D supplementation on the development of osteopenia in young rats under mild calcium deficiency. Sixty female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into six groups with 10 rats in each group: baseline control, 0.5% (normal) calcium diet, 0.1% (low) calcium diet, 0.1% calcium diet + vitamin K (30 mg/100 g, food intake), 0.1% calcium diet + vitamin D (25 microg/100 g, food intake), and 0.1% calcium diet + K + D. After 10 weeks of feeding, serum calcium, 25-hydroxyvitamin D(3) [25 (OH) D(3)], 1,25-dihydroxyvitamin D(3) [1,25 (OH)(2) D(3)], and parathyroid hormone (PTH) levels were measured, and intestinal calcium absorption and renal calcium reabsorption were evaluated. Bone histomorphometric analyses were performed on cortical bone of the tibial shaft and cancellous bone of the proximal tibia. Calcium deficiency induced hypocalcemia, increased serum PTH and 1,25 (OH)(2) D(3) levels with decreased serum 25 (OH) D(3) level, stimulated intestinal calcium absorption and renal calcium reabsorption, and reduced maturation-related cortical bone gain as a result of decreased periosteal bone gain and enlarged marrow cavity but did not significantly influence maturation-related cancellous bone gain. Vitamin K supplementation in calcium-deficient rats stimulated renal calcium reabsorption, retarded the abnormal elevation of serum PTH level, increased maturation-related cancellous bone gain, and retarded the reduction in maturation-related cortical bone gain. On the other hand, vitamin D supplementation in calcium-deficient rats stimulated intestinal calcium absorption via increased serum 1,25 (OH)(2) D(3) level with prevention of the abnormal elevation of serum PTH level, prevented hypocalcemia, reduced the maturation-related cancellous bone gain, and prevented the reduction in periosteal bone gain and enhanced enlargement of the marrow cavity with no significant effect on the reduction in maturation-related cortical bone gain. However, no synergistic effect of vitamin K and vitamin D on intestinal calcium absorption, renal calcium reabsorption, and cancellous and cortical bone mass was found. This study shows the differential effects of vitamin K and vitamin D supplementation on the development of osteopenia in young rats under mild calcium deficiency. Vitamin K supplementation stimulates renal calcium reabsorption, increases maturation-related cancellous bone gain, and retards the reduction in maturation-related cortical bone gain, whereas vitamin D supplementation stimulates intestinal calcium absorption and prevents the reduction in maturation-related periosteal bone gain by inducing accumulation of calcium from cancellous and endocortical bone. 相似文献
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K Endo K Katsumata M Hirata T Masaki N Kubodera T Nakamura K Ikeda E Ogata 《Journal of bone and mineral research》2000,15(1):175-181
The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its analogue 22-oxa-1,25(OH)2D3 (22-oxacalcitriol) (OCT) on calcium and bone metabolism were examined in an animal model of hypercalcemia with continuous infusion of parathyroid hormone-related peptide (PTHrP), to determine whether active vitamin D could counteract the skeletal action of PTHrP in addition to its reported effect in suppressing the production of PTHrP in cancer cells. Parathyroid glands were removed from 8-week-old Sprague-Dawley rats to eliminate the confounding effects of endogenous PTH. Animals were then continuously infused with human PTHrP(1-34) at a constant rate via osmotic minipumps for 2 weeks, and at the same time treated orally or intravenously with OCT or 1,25(OH)2D3 four to nine times during the 2-week period. Under these conditions, OCT and, surprisingly, 1,25(OH)2D3 alleviated hypercalcemia in a dose-dependent manner. 1,25(OH)2D3 and OCT suppressed the urinary excretion of deoxypyridinoline, although they did not affect renal calcium handling, suggesting that the antihypercalcemic effect is attributable to the inhibition of bone resorption. These active vitamin D compounds also counteracted the effects of PTHrP at the proximal renal tubules, as reflected by a decrease in phosphate excretion. Histomorphometric analysis of bone revealed a dose-related decrease in parameters of bone resorption. These results suggest that 1,25(OH)2D3 as well as OCT has the potential to alleviate hypercalcemia, at least in part, through the inhibition of bone resorption in hypercalcemic rats with constant PTHrP levels. We propose that the main function of active vitamin D in high bone-turnover states is to inhibit bone resorption, and this may have important implications for the understanding of the role of active vitamin D in the treatment of metabolic bone diseases, such as osteoporosis. 相似文献
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The kidney is the major, if not sole, site for the production of 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active form of vitamin D that can stimulate calcium reabsorption in the kidney and may provide renoprotective benefits. The biological effects of 1,25(OH)(2)D(3) are mediated through a nuclear hormone receptor, known as the vitamin D receptor (VDR). It is well accepted that the VDR is present in the distal renal convoluted tubule cells; however, whether VDR is present in other kidney cell types is uncertain. Using a highly specific and sensitive anti-VDR antibody, we determined its distribution in the mouse kidney by immunohistochemistry. Our results show that the VDR is not only present in the distal but is also found in the proximal tubules, but at 24-fold lower levels. The VDR was also found in the macula densa of the juxtaglomerular apparatus, glomerular parietal epithelial cells, and podocytes. In contrast, the VDR is either very low or absent in interstitial fibroblasts, glomerular mesangial cells, and juxtaglomerular cells. Thus, identification of VDR in the proximal tubule, macula densa, and podocytes suggests that 1,25(OH)(2)D(3) plays a direct role in these cells under normal conditions. 相似文献