Effects of long-term administration of vitamin D3 analogs to mice

Smith, EA; Frankenburg, EP; Goldstein, SA; Koshizuka, Kozo; Elstner, E; Said, Jonathan; Kubota, Tetsuya; Uskoković, Milan R.; Koeffler, H. Phillip

doi:10.1677/joe.0.1650163

Cited by 36 publications

(27 citation statements)

References 33 publications

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“…Interestingly, a recent study of longterm treatment of mice with 1,25-(OH) 2 D 3 demonstrated a decrease in cortical thickness and crosssectional area and a 50% reduction in stiffness (28), which is in line with the current observations. We hypothesize that the bone phenotype of the TRPV5 -/-mice, due to prolonged elevated 1,25-(OH) 2 D 3 levels, develops and progresses throughout life.…”

Section: Resultssupporting

confidence: 92%

Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Hoenderop¹,

Leeuwen²,

Eerden³

et al. 2003

J. Clin. Invest.

225

230

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contributed equally to this work. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: parathyroid hormone (PTH); 1,25-dihydroxycholecalciferol (1,25-(OH)2D3); transient receptor potential (TRP); TRP cation channel subfamily V, member 5 (TRPV5); TRP cation channel subfamily V, member 6 (TRPV6); last loop of proximal tubules (LPT); hypoxanthine-guanine phosphoribosyl transferase (HPRT); bone volume (BV); total bone marrow volume including trabeculae (TV); trabecular bone volume fraction (BV/TV); trabecular thickness (Tb.Th); trabecular number (Tb.N); connectivity density (CD); structure model index (SMI); cortical volume (Ct.V); endocortical volume (Ec.V); total diaphyseal volume (Dp.V), cortical thickness (Ct.Th); cortical bone volume fraction (Ct.V/Dp.V); moment of inertia (MOI); Tartrate-resistant acid phosphatase (TRAP); number of osteoclasts per bone surface area (N.Oc/BS); surface area of osteoclasts per bone surface area (Oc.S/BS); arginine vasopressin (AVP); Na + -Ca 2+ exchanger (NCX1); vitamin D receptor (VDR). IntroductionCa 2+ is the most abundant cation in the human body and serves a number of important physiological functions, including fertilization, synaptic transmission, muscle contraction, blood clotting, and bone mineralization. The extracellular Ca 2+ concentration is controlled by the kidney, intestine, and bone through the action of the calciotropic hormones, including parathyroid hormone (PTH) and 1,25-dihydroxycholecalciferol (1,25-(OH) 2 D 3 ). In humans, the daily dietary Ca 2+ intake is less than 1,000 mg, of which only 30% is absorbed in the intestinal tract. This percentage is significantly enhanced during growth, pregnancy, and lactation by increased levels of circulating 1,25-(OH) 2 D 3 . Although there is continuous turnover of bone mass, there is no net gain or loss of Ca 2+ from bone in a young and healthy individual. This indicates that healthy adults excrete a maximum of 300 mg Ca 2+ in the urine to balance the intestinal Ca 2+ uptake and that the remaining 98% of the Ca 2+ filtered in the glomeruli is reabsorbed along the nephron. The molecular mechanism responsible for Ca 2+ absorption in the small intestine and the kidney was elusive for a long time.Renal Ca 2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 Ca 2+ ions play a fundamental role in many cellular processes, and the extracellular concentration of Ca 2+ is kept under strict control to allow the proper physiological functions to take place. The kidney, small intestine, and bone determine the Ca 2+ flux to the extracellular Ca 2+ pool in a concerted fashion. Transient receptor potential (TRP) cation channel subfamily V, members 5 and 6 (TRPV5 and TRPV6) have recently been postulated to be the molecular gatekeepers facilitating Ca 2+ influx in these tissues and are members of the TRP family, which mediates diverse biological effects ranging from pain perception to male aggression. Genetic ablation of TRPV5 in the mouse allowed u...

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Section: Resultssupporting

confidence: 92%

Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Hoenderop¹,

Leeuwen²,

Eerden³

et al. 2003

J. Clin. Invest.

225

230

View full text Add to dashboard Cite

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“…injections of vitamin D 3 derivatives alone and the control animals injected with vehicle (ethanol) were kept on the standard diet. 43,48 Animals allotted to the groups for oral administration of rosemary extract alone received the same diet supplemented with 1% (w/w) rosemary extract and ethanol injections. For combination treatment, mice were fed diet containing rosemary extract and injected with Ro25-4020.…”

Section: Experimental Groups and Dietmentioning

confidence: 99%

“…in 100 ll PBS, 3 times a week (Sunday, Tuesday and Thursday), according to the published protocol. 15,43,48 Cell inoculation and tumorigenicity assay Following acclimatization, mice were inoculated i.p. with 1 3 10 5 WEHI-3B D 2 cells in 100 ll sterile PBS 15 and randomly assigned to control and treatment groups (10 animals per group).…”

Section: Administration Of Vitamin D Derivativesmentioning

confidence: 99%

Cooperative antitumor effects of vitamin D₃ derivatives and rosemary preparations in a mouse model of myeloid leukemia

Sharabani

Izumchenko

Wang

et al. 2006

Intl Journal of Cancer

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1a,25-dihydroxyvitamin D 3 (1,25D 3 ) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D 3 in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D 2 murine myelomonocytic leukemia cells induced by 1 nM 1,25D 3 or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 lM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G01G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 lg Ro25-4020 in Balb/c mice bearing WEHI-3B D 2 tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 lg Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia. ' 2006 Wiley-Liss, Inc.

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“…Whereas physiological doses of 1,25(OH) 2 D 3 inhibit PTH-induced bone resorption, 1,25(OH) 2 D 3 has been suggested to stimulate bone resorption by enhancing osteoclast formation when present at supraphysiological levels. (28,29) Indeed, both the number of mature osteoclasts and osteoclast precursors in bone marrow of TRPV5 −/− mice were increased, indicating an accelerated osteoclast differentiation pathway in the presence of hypervitaminosis D in these mice. (6) Taken together, these data suggest that the increased 1,25(OH) 2 D 3 levels not only lead to Ca 2+ hyperabsorption but might also rescue the impaired osteoclast function, concurrently resulting in the maintenance of normocalcemia.…”

Section: Alendronate In Trpv5 −/− Micementioning

confidence: 97%

Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5−/− Mice

Nijenhuis

Eerden

Hoenderop

et al. 2008

Journal of Bone and Mineral Research

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TRPV5 is a Ca 2+ -selective channel involved in transcellular Ca 2+ absorption expressed in kidney and in the ruffled border of osteoclasts. Studies in hypercalciuric TRPV5 knockout (TRPV5 −/− ) mice, which display significantly increased vitamin D levels, showed that TRPV5 ablation increases number and size of osteoclasts but impairs osteoclast-mediated bone resorption. The latter is not in line with the observed decreased bone thickness in TRPV5 −/− mice. Bisphosphonates also inhibit osteoclast-mediated bone resorption. The aim of this study was to evaluate the effect of alendronate on the expression of the Ca 2+ transporters in bone, kidney, and duodenum and, importantly, the bone phenotype in TRPV5 −/− mice. Wildtype (TRPV5 +/+ ) and TRPV5−/− mice were treated during 10 wk with 2 mg/kg alendronate or vehicle weekly and housed in metabolic cages at the end of treatment. Urine and blood samples were taken for biochemical analysis, and duodenum, kidney, and femur were sampled. Expression of Ca 2+ transporters and osteoclast ruffled border transporters in bone and cultured osteoclasts was determined by QPCR analysis. Femurs were scanned using CT, and resorption pit assays were performed in bone marrow cultures isolated from TRPV5 +/+ and TRPV5 −/− mice. Alendronate treatment enhanced bone thickness in TRPV5 +/+ mice but also normalized the disturbed bone morphometry parameters in TRPV5 −/− mice. Bone TRPV5 expression was specifically enhanced by alendronate, whereas the expression of Ca 2+ transporters in kidney and intestine was not altered. The expression of the osteoclast ruffled border membrane proteins chloride channel 7 (CLC-7) and the vacuolar H + -ATPase did not differ between both genotypes, but alendronate significantly enhanced the expression and PTH levels in TRPV5 −/− mice. The expression of TRPV5, CLC-7, and H + -ATPase in osteoclast cultures was not affected by alendronate. The number of resorption pits was reduced in TRPV5 −/− bone marrow cultures, but the response to vitamin D was similar to that in TRPV5 +/+ cultures. The alendronate-induced upregulation of TRPV5 in bone together with the decreased resorptive capacity of TRPV5 −/− osteoclasts in vitro suggests that TRPV5 has an important role in osteoclast function. However, our data indicate that significant bone resorption still occurs in TRPV5 −/− mice, because alendronate treatment normalized bone thickness in these mice. Thus, TRPV5 −/− mice are able to rescue the resulting defect in osteoclast-mediated bone resorption, possibly mediated by the long-term hypervitaminosis D or other (non)hormonal compensatory mechanisms.

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Effects of long-term administration of vitamin D3 analogs to mice

Cited by 36 publications

References 33 publications

Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Cooperative antitumor effects of vitamin D₃ derivatives and rosemary preparations in a mouse model of myeloid leukemia

Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5−/− Mice

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Effects of long-term administration of vitamin D3 analogs to mice

Cited by 36 publications

References 33 publications

Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia

Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5−/− Mice

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Cooperative antitumor effects of vitamin D₃ derivatives and rosemary preparations in a mouse model of myeloid leukemia