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PubMed2001

Novel nonsecosteroidal vitamin D receptor modulator inhibits the growth of LNCaP xenograft tumors in athymic mice without increased serum calcium.

BACKGROUND: We recently reported on novel vitamin D receptor (VDR) modulators that are structurally distinct from the secosteroid 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the endogenous activator of VDR. One of these compounds, LG190119, was tested for the ability to inhibit the growth of LNCaP human prostate cancer cell-derived tumors in athymic mice. METHODS: In one study, athymic mice with established LNCaP xenograft tumors were dosed orally every day with LG190119 (3 or 10 mg/kg) or with a synthetic analog of 1,25(OH)(2)D(3), EB1089 (1 microg/kg), for 15 days. In another study ("prevention mode"), oral administration (every other day) of 10 mg/kg LG190119 or a non-hypercalcemic dose of 1,25(OH)(2)D(3) (0.5 microg/kg) was initiated prior to tumor development and continued for 84 days. In both studies, tumor volumes, mouse weights, and serum calcium levels were measured. RESULTS: In the established tumor study, LG190119 at each dose resulted in significant tumor growth inhibition without hypercalcemia at both 10 and 15 days. EB1089 treatment resulted in significant tumor growth inhibition only at Day 10 and resulted in hypercalcemia at Day 15. In the prevention-mode study, LG190119 markedly slowed tumor growth without increased serum calcium in comparison with either vehicle or 1,25(OH)(2)D(3) treatment (P < 0.001). CONCLUSIONS: LG190119 effectively inhibited LNCaP xenograft tumor growth without increased serum calcium levels or any other apparent side effects. Compounds of this class may represent promising new therapeutics for treatment of prostate cancer and other cancers with fewer undesirable side effects than currently used drugs.

Animals↗
PubMed2000

1alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and 1alpha,25-dihydroxy-16-ene-23-yne-20-epi-vitamin D3: analogs of 1alpha,25-dihydroxyvitamin D3 that resist metabolism through the C-24 oxidation pathway are metabolized through the C-3 epimerization pathway.

The secosteroid hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the previously well established main side chain modification pathway, is initiated by hydroxylation at C-24 of the side chain. The C-3 epimerization pathway, the newly discovered A-ring modification pathway, is initiated by epimerization of the hydroxyl group at C-3 of the A-ring. The end products of the metabolism of 1alpha,25(OH)2D3 through the C-24 oxidation and the C-3 epimerization pathways are calcitroic acid and 1alpha,25-dihydroxy-3-epi-vitamin-D3 respectively. During the past two decades, numerous noncalcemic analogs of 1alpha,25(OH)2D3 were synthesized. Several of the analogs have altered side chain structures and as a result some of these analogs have been shown to resist their metabolism through side chain modifications. For example, two of the analogs, namely, 1alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 [1alpha,25(OH)2-16-ene-23-yne-D3] and 1alpha,25-dihydroxy-16-ene-23-yne-20-epi-vitamin D3 [1alpha,25(OH)2-16-ene-23-yne-20-epi-D3], have been shown to resist their metabolism through the C-24 oxidation pathway. However, the possibility of the metabolism of these two analogs through the C-3 epimerization pathway has not been studied. Therefore, in our present study, we investigated the metabolism of these two analogs in rat osteosarcoma cells (UMR 106) which are known to express the C-3 epimerization pathway. The results of our study indicate that both analogs [1alpha,25(OH)2-16-ene-23-yne-D3 and 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3] are metabolized through the C-3 epimerization pathway in UMR 106 cells. The identity of the C-3 epimer of 1alpha,25(OH)2-16-ene-23-yne-D3 [1alpha,25(OH)2-16-ene-23-yne-3-epi-D3] was confirmed by GC/MS analysis and its comigration with synthetic 1alpha,25(OH)2-16-ene-23-yne-3-epi-D3 on both straight and reverse-phase HPLC systems. The identity of the C-3 epimer of 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3 [1alpha,25(OH)2-16-ene-23-yne-20-epi-3-epi-D3] was confirmed by GC/MS and 1H NMR analysis. Thus, we indicate that vitamin D analogs which resist their metabolism through the C-24 oxidation pathway, have the potential to be metabolized through the C-3 epimerization pathway. In our present study, we also noted that the rate of C-3 epimerization of 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3 is about 10 times greater than the rate of C-3 epimerization of 1alpha,25(OH)2-16-ene-23-yne-D3. Thus, we indicate for the first time that certain structural modifications of the side chain such as 20-epi modification can alter significantly the rate of C-3 epimerization of vitamin D compounds.

Animals↗
PubMed1998

Studies suggesting the participation of protein kinase A in 1, 25(OH)2-vitamin D3-dependent protein phosphorylation in cardiac muscle.

We have previously established that the secosteroid hormone 1alpha, 25-dihydroxy-vitamin D3 [1,25(OH)2D 3] rapidly stimulates dihydropyridine-sensitive calcium channel-mediated Ca2+ influx in chick cardiac muscle by a non-genomic action which is accompanied by phosphorylation of microsomal proteins. In the present study, we investigated the participation of the cyclic AMP/protein kinase A (PKA) signalling pathway in hormone-induced changes on protein phosphorylation in chick heart tissue. A major increase in the phosphorylation of a microsomal protein of 45 kDa, and, to a lesser extent, of a protein of 70 kDa, was observed after incubation with [gamma-32P]ATP of membranes isolated from heart thin slices (HTS) pretreated for 1-5 min with 1,25(OH)2D3. This effect was dose- and time-dependent, reaching a maximum after 3 min and at the physiological concentrations of 10(-10) and 10(-11) M. 1,25(OH)2D3 steadily increased cellular cAMP levels as a function of the dose (10( -12)-10(-9) M). The specific agonist of PKA, Sp-cAMPS and the PKA catalytic subunit stimulated the phosphorylation of the same membrane proteins as the hormone. The 1alpha,25-dihydroxy-vitamin D3-dependent changes in microsomal protein phosphorylation were diminished by the specific PKA inhibitor, Rp-cAMPS. In addition, the PKA activity ratio (-cAMP/+cAMP) increased 60% above the control after treatment of HTS with 10(-11) M 1,25(OH)2D3. The data obtained clearly indicate that activation of the cAMP/PKA signalling pathway mediates the stimulation of protein phosphorylation by 1alpha, 25-dihydroxy-vitamin D3 in chick cardiac muscle.

Animals↗
PubMed1994

Vitamin D receptors in breast cancer cells.

1,25-(OH)2-Vitamin D3, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)2-vitamin D3 has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to analyze vitamin D receptor level in breast cancer cells as a marker of differentiation and as a predictor of growth inhibition by 1,25-(OH)2-vitamin D3. VDR messenger RNA was found to be present in relatively high levels in well-differentiated cells and in low levels in poorly differentiated cells. All cell lines had detectable VDR mRNA. Radiolabeled ligand binding assay showed a similar pattern. MCF-7 and T47D cells, which express VDR at moderate levels, showed significant growth inhibition by 10(-9) M1,25-(OH)2-vitamin D3 (p < 0.05). MDA-MB-231 cells, which have very low levels of VDR, demonstrated no growth inhibition by 1,25-(OH)2-vitamin D3 at concentrations up to 10(-6) M. Based on these results it can be stated that VDR expression is lost with de-differentiation and that receptor is essential for the antiproliferative response to 1,25-(OH)2-vitamin D3.

Adenocarcinoma↗
PubMed1986

Mechanisms of 1,25(OH)2D3-induced rapid changes of membrane potential in proximal tubule: role of Ca2+-dependent K+ channels.

Eleven different secosteroids or steroids (10(-10) to 10(-8) M) were acutely and reversibly introduced in solutions delivered to the lumen of single proximal tubules of the amphibian Necturus kidney while recording basolateral cell membrane potential Vm. Seven of these molecules (1,25(OH)2D3, 25(OH)D3, 24,25(OH)2D3, 5,6-trans-25(OH)D3, 19-diol-cholesterol, estradiol and testosterone) resulted in changes of Vm (delta Vm) occurring in a few seconds, the largest delta Vm being observed with 1,25(OH)2D3, +6.5 +/- 0.75 mV (n = 19); these seven (seco)steroids, but not the four inactive sterols (vitamin D3, cholesterol, 1 alpha D3 and aldosterone) possess a hydroxyl group on at least one carbon of the C17 to C25 lateral chain of the sterol ring. The delta Vm effect was present in Na+-free or Cl-free media, but it was abolished in HCO3-free media. Depolarization of cell membrane potential by addition of glucose, 11 mM, in luminal perfusion fluid abolished the 1,25(OH)2D3-evoked delta Vm effect, suggesting dependence of the latter on the absolute value of membrane potential. Barium, a blocking agent of K+ conductances, suppressed the 1,25(OH)2D3-evoked delta Vm effect, even when the proper effects of barium of cell membrane potential were canceled by current clamp. Pretreatment with quinine, a putative blocker of Ca2+-dependent K+ channels also abolished the 1,25(OH)2D3-evoked depolarization. Such observations are consistent with the presence of Ca2+-dependent K+ channels at the apical cell membrane of the proximal tubule, these channels being inactivated by 1,25(OH)2D3 and probably by other (seco)steroids.

Animals↗
PubMed1983

Reversal of decreased phosphorylation of sarcoplasmic reticulum calcium transport ATPase by 1,25-dihydroxycholecalciferol in experimental uremia.

When compared to that from sham-operated controls, sarcoplasmic reticulum isolated from skeletal muscle of uremic rabbits had a lower rate of calcium uptake and storing capacity. In vivo administration of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] restored the values in uremic animals toward normal. To obtain information about the mechanisms responsible for these differences, phosphorylation of the calcium transport ATPase was studied. The steady-state levels of phosphoprotein in uremic membranes were lower and returned to normal when the secosteroid was administered. Electrophoresis of the membranes phosphorylated with 32P-inosine triphosphate (32P-ITP) showed that the differences were related to a 100,000 dalton protein. The rate of phosphoprotein formation, determined with 32P-ITP and at 0 degrees C, was considerably lower in uremic than in control animals. Pretreatment with 1,25(OH)2D3 prevented this change. The hypothesis is advanced that the vitamin D metabolite affects the steady-state concentration and rate constant of formation of active sites in the Ca-ATPase. These results may partly explain the altered Ca transport function of the sarcoplasmic reticulum in experimental uremia.

Animals↗
PubMedDate not supplied

Pre-clinical evidence and clinical translation of benign prostatic hyperplasia treatment by the vitamin D receptor agonist BXL-628 (Elocalcitol).

The active form of vitamin D, 1,25-dihydroxyvitamin D3, is a secosteroid hormone that binds to the vitamin D receptor (VDR), a member of the superfamily of nuclear receptors, and exerts a number of diverse biological functions. The natural hormone and synthetic VDR agonists are well known for their capacity to control calcium and bone metabolism, but they also regulate proliferation and differentiation of many cell types, and possess exquisite immunoregulatory properties, mostly by targeting dendritic cells (DC) and T cells. These properties have been clinically exploited in the treatment of different diseases, from secondary hyperparathyroidism to osteoporosis to psoriasis. The VDR is expressed by most cell types, including cells of the urogenital system such as prostate and bladder cells. In particular, the prostate has been recognized as a target organ of VDR agonists and represents an extra-renal synthesis site of 1,25-dihydroxyvitamin D3, but its capacity to respond to VDR agonists has, so far, been probed only for the treatment of prostate cancer. We have taken a different approach, and have analysed the capacity of VDR agonists to treat benign prostatic hyperplasia (BPH), a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic component responsible for urinary irritative symptoms, and a possible inflammatory component. Pre-clinical data reviewed here demonstrate that VDR agonists, and notably BXL-628 (Elocalcitol), reduce the static component of BPH by inhibiting the activity of intra-prostatic growth factors downstream of the androgen receptor, and the dynamic component by targeting bladder cells. These data have led to a proof-of-concept clinical study that has successfully shown arrest of prostate growth in BPH patients treated with BXL-628. Ongoing clinical studies will assess the capacity of this VDR agonist to reduce symptoms and ameliorate flow parameters in BPH-affected individuals. The pronounced effects of BXL-628 on bladder smooth muscle cells and its anti-inflammatory properties indeed anticipate beneficial effects also on BPH-related lower urinary tract symptoms.

Androgens↗
PubMed1997

Effect of 1,25(OH)2 vitamin D3 on circulating insulin-like growth factor-I and beta 2 microglobulin in patients with osteoporosis.

To test the hypothesis that growth factors mediate the stimulatory effect of 1,25(OH)2 vitamin D3 [1,25(OH)2D3] on bone remodeling in osteoporosis, the authors studied the effect of the secosteroid administration in two doses (1 microgram/day and 2 micrograms/day) for 14 days on circulating insulin-like growth factor-I (IGF-I), beta 2 microglobulin, and osteocalcin in 18 osteoporotic women. The biological effectiveness of the treatment was controlled by a decline of serum intact parathyroid hormone. Compared with the values before treatment, 1,25(OH)2D3 increased means of plasma IGF-I, beta 2 microglobulin, and serum osteocalcin significantly; however, the effects were only apparent after the higher dose of the drug (169 +/- 26 versus 134 +/- 28 ng/ml, P < 0.01; 2.08 +/- 0.1 versus 1.92 +/- 0.1 micrograms/ml, P < 0.05; and 8.5 +/- 1.3 versus 5.4 +/- 1.1 ng/ml, P < 0.01, respectively). The authors conclude that exogenous 1,25(OH)2D3 promotes the production of IGF-I and beta 2 microglobulin in osteoporotic patients in parallel to the marker of osteoblastic function, osteocalcin, which supports the tested hypothesis.

Calcitriol↗
PubMed1999

TGFbeta1 regulates 25-hydroxyvitamin D3 1alpha- and 24-hydroxylase activity in cultured growth plate chondrocytes in a maturation-dependent manner.

Chondrocytes metabolize 25-(OH)D3 to the two active dihydroxylated forms of the secosteroid, 1,25-(OH)2D3 and 24,25-(OH)2D3. The aim of the present study was to examine the activity of the enzymes responsible for this metabolism, 1alpha-hydroxylase and 24R-hydroxylase, and their regulation by TGFbeta1. Basal 1alpha- and 24R-hydroxylase activities were measured in homogenates of confluent, fourth passage rat costochondral resting zone and growth zone chondrocytes and mouse cortico-tubular cells (MCT) were used as a positive control. The cells were harvested and homogenized in buffer optimized to maintain the activity and stability of the hydroxylases. Homogenates were incubated for 90 minutes and 1alpha- and 24R-hydroxylase activities determined by measuring the conversion of [3H]-25-(OH)D3 to [3H]-1,25-(OH)2D3 and [3H]-24,25-(OH)2D3 using an HPLC with an inline radioisotope detector. Resting zone cells were also treated with various concentrations of recombinant human TGFbeta1 for 24 hours, and enzyme activity in total cell homogenates as well as 24-hydroxylase mRNA levels were determined. In addition, [3H]-1,25-(OH)2D3 and [3H]-24,25-(OH)2D3 released into the conditioned media by resting zone chondrocyte cultures in response to TGFbeta1 were measured. In culture, all three cell types were found to contain 1alpha- and 24R-hydroxylase activities. Basal 1alpha-hydroxylase specific activity was significantly higher than 24R-hydroxylase specific activity in all cells. RT-PCR confirmed that resting zone and growth zone cells expressed mRNA for 24R-hydroxylase. Treatment of resting zone cells with TGFbeta1 increased 24R-hydroxylase mRNA levels in a dose-dependent manner. TGFbeta1 also increased 24R-hydroxylase activity 2- to 5-fold and decreased 1alpha-hydroxylase activity by 20-30%. Similar changes were observed with MCT cells, but not growth zone cells. Production of [3H]-24,25-(OH)2D3 by resting zone cells increased with TGFbeta1 treatment, while [3H]-1,25-(OH)2D3 production decreased. The effect was time- and dose-dependent, correlating with hydroxylase activity and 24-hydroxylase gene expression. These results demonstrate that growth plate chondrocytes contain the necessary enzymes to produce 1, 25-(OH)2D3 and 24,25-(OH)2D3 from 25-(OH)D3. In addition, the activity of these enzymes in resting zone cells, but not growth zone cells, is regulated by TGFbeta1 by increasing gene transcription, indicating that cell maturation-dependent autocrine/paracrine pathways exist for regulating vitamin D metabolite production.

Animals↗
PubMed1979

Vitamin D metabolism and calcium absorption.

Vitamin D along with parathyroid hormone (PTH) and calcitonin (CT) are the three principal effectors of calcium and phosphorus homeostasis. The secosteroid, vitamin D3, is subject to metabolic conversion to its biologically active form(s) 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] prior to initiation of its physiologic responses in the intestine and skeletal system. The production of 1,25(OH)2D3 is stringently regulated by a variety of endocrine signals including PTH as well as the "calcium needs" of the organism. At the target intestine, 1,25-(OH)2D3 stimulates the intestinal absorption of calcium via a mechanism analogous to that of other steroid hormones. Definitive biochemical evidence exists supporting the existence in the intestine of a highly specific protein receptor for 1,25(OH)2D3. After formation of the steroid-receptor complex, it migrates to the nucleus of the cell and stimulates messenger-RNA synthesis for proteins (including a calcium-binding protein) which are necessary for the generation of the biologic response. Current efforts to biochemically characterize vitamin D-mediated intestinal calcium transport include efforts to understand the role of calcium-binding protein in this process, as well as to identify other protein components present either in the brush border or basal lateral membranes.

Adenosine Triphosphatases↗
PubMed1982

A rapid and simple method for the measurement of plasma 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 using Sep-Pak C18 cartridges and a single high-performance liquid chromatographic step.

A simple one step high-performance liquid chromatographic (HPLC) procedure for the analysis of plasma concentrations of 25-hydroxyvitamin D3 (25-OHD3) and 25-hydroxyvitamin D2 (25-OHD2) is described. Plasma (2-4 ml) was extracted with methyl cyanide which was passed through a Sep-Pak C18 cartridge, washed with methanol:water (70:30, v/v) and the 25-OHD fraction eluted with methyl cyanide. After isomerisation to their isotachysterol derivatives, the secosteroids were estimated using a straight-phase HPLC system, monitoring the eluent at 301 nm. Radioactive 25-OHD3, added to plasma at the start of the procedure, was used to correct for losses. Recovery of added 25-OHD3 was quantitative and values obtained using this method were similar to those obtained on the same plasma samples using a mass fragmentographic technique. Normal ranges were similar to those described by other workers and within- (5.8% for 25-OHD3) and between-(8.0% for 25-OHD3) batch reproducibilities were satisfactory.

25-Hydroxyvitamin D 2↗
PubMed1991

Variations of vitamin D-like reactivity in the crustacean Orchestia cavimana during the molt cycle.

An investigation into vitamin D-like molecules has been performed on whole extracts of the terrestrial amphipod Orchestia cavimana, using a sensitive nonequilibrium assay employing 1,25-(OH)2 D receptor from calf thymus. Relatively large amounts of these secosteroid-like molecules were observed and they varied in concentration according to the stages of the molt cycle. The amplitude of these variations reaches a ratio of about 40 from the minimum in premolt to the intermolt sharp peak.

Animals↗
PubMed1987

The cholecalciferol sulphate system in mammals.

7-Dehydrocholesterol sulphate has been identified in human and rat skin. The compound was isolated by anion exchange chromatography and following hydrolysis it was characterized by high-performance liquid chromatography and gas chromatography-mass spectrometry. Experiments with rats showed that 7-dehydrocholesterol sulphate can serve as a precursor of cholecalciferol sulphate and 25-hydroxy-cholecalciferol 3-sulphate, the latter compound being present in significant amounts in human blood. The sulphated sterols identified represent a previously unknown secosteroid system in mammals.

Animals↗
PubMed1988

Vitamin D metabolism in human pregnancy. Concentrations of free and sulphated 25-hydroxyvitamin D3 in maternal and fetal plasma at term.

The concentrations of free and sulphated 25-hydroxyvitamin D3 in 20 paired maternal-cord plasma samples obtained at delivery have been determined. The compounds were isolated by liquid-solid extraction at elevated temperature, and the sulphate was purified by anion exchange chromatography prior to hydrolysis and analysis by high-performance liquid chromatography. The study shows that unconjugated 25-hydroxyvitamin D3 is predominant in maternal plasma (mean 20 ng/ml) whereas the sulphate is the major form of vitamin D3 in fetal circulation (mean 21 ng/ml plasma). The total concentration of the two compounds in cord plasma (mean 35 ng/ml) was significantly higher than that in maternal plasma (mean 30 ng/ml). Positive correlations were obtained between maternal and cord plasma levels of free 25-hydroxyvitamin D3, between maternal and cord plasma levels of sulphated 25-hydroxyvitamin D3 and between plasma levels of the maternal free compound and the fetal sulphate. There was also a relationship between the levels of free and sulphated 25-hydroxyvitamin D3 in cord plasma. The results suggest that sulphation may be a physiologically important reaction for deactivating and/or trapping secosteroids in the fetus.

Adult↗
PubMed1984

1 alpha, 25-dihydroxycholecalciferol and human histiocytic lymphoma cell line (U-937): the presence of receptor and inhibition of proliferation.

Human histiocytic lymphoma cells (U-937) contain high affinity binding protein for 1 alpha, 25-dihydroxycholecalciferol. The Kd (0.2 nM) and sedimentation coefficient on sucrose gradients (3.7 S) are similar to those reported for 1 alpha, 25-dihydroxycholecalciferol receptor in other tissues. This secosteroid added to the culture was able to inhibit cell proliferation in a dose dependent manner. Differentiation-associated properties such as phagocytic ability, C3 rosette formation, positive reaction for alpha- naphtyl acetate esterase as well as electron microscopy examination indicate that 1 alpha, 25-dihydroxycholecalciferol induces in vitro monocyte-macrophage differentiation in this monoblast-like cell line.

Calcitriol↗
PubMed1987

Phorbol esters, but not the hormonal form of vitamin D, induce changes in protein kinase C during differentiation of human histiocytic lymphoma cell line (U-937).

Human histiocytic lymphoma cells (U-937) undergo similar differentiation when incubated with the phorbol ester 12-0-tetradecanoyl phorbol-13-acetate (TPA) and 1,25-dihydroxycholecalciferol. In this action, TPA somehow implicates calcium-sensitive and phospholipid-dependent protein kinase (protein kinase C), which is rapidly and significantly affected by this inducer. On the contrary, 1,25-dihydroxycholecalciferol in its differentiating action does not involve protein kinase C thus suggesting that the secosteroid induces monocytic differentiation possible through a different mechanism of that of phorbol ester.

Antibodies, Monoclonal↗
PubMed1993

Stimulatory effect of 1,25-dihydroxyvitamin D3 on calcium handling and insulin secretion by islets from vitamin D3-deficient rats.

Among the various vitamin D3 metabolites, 1,25-(OH)2D3 is the specific secosteroid hormone that can enhance, in vitro, the weak insulin response to glucose of islets from vitamin D3-deficient rats. Because this potentiating effect is preceded by an increase in Ca2+ handling, several putative sites of action were studied by measuring 45Ca2+ and 86Rb+ (as K+ tracer) efflux during perifusions in the presence of various stimuli known to affect Ca2+ movements in different ways: high glucose without calcium, high calcium without glucose, high potassium, or barium-theophylline without calcium or glucose. The present results show that 1,25-(OH)2D3 may activate Ca2+ handling by at least two mechanisms: (1) an increase of Ca2+ entry via voltage-dependent Ca2+ channels in the experiments in which extracellular Ca2+ was present and where Ca2+ channels were opened; this 1,25-(OH)2D3 influence on Ca2+ channels was not mediated by a possible indirect influence on K+ channels because 86Rb+ fluxes were never observed to be affected by the steroid; (2) an enhancement of 45Ca2+ mobilization from intracellular stores as suggested by barium-theophylline stimulation and probably also via the Ca2+ stimulus. Both of these 1,25-(OH)2D3 influences tended to provide more calcium to the B cell of vitamin D3-deficient rats. But this prerequisite was not sufficient in itself to potentiate the insulin response; indeed, experiments with barium-theophylline suggested that 1,25-(OH)2D3 may also activate a cAMP-dependent exocytosis process.

Animals↗
PubMed1996

Regulation of NGF, BDNF and LNGFR gene expression in ROS 17/2.8 cells.

The secosteroid hormone 1.25-dihydroxyvitamin D3 (1,25(OH)2D3) has been recently shown to enhance the synthesis of NGF to mouse L929 fibroblasts. In view of the critical role of 1,25(OH)2D3 on bone metabolism, it has been investigated if ROS 17/2.8 osteoblastic cells were able to express the nerve growth factor (NGF) gene and if this process was responsive to 1,25(OH)2D3. Results indicate that these cells respond in a dose-dependent manner to the presence of 1,25(OH)2D3 by an increase in NGF mRNA levels. However, the phorbol ester PMA, previously reported to augment the synthesis of NGF via the recruitment of AP-1 complexes, depressed the expression of the NGF gene in ROS cells. In contrast, the mRNA levels of an NGF-related trophic factor, brain-derived neurotrophic factor (BDNF), was increased by PMA but not following 1,25(OH)2D3 treatment. Binding of 125I-NGF to ROS cells displayed the properties of a low affinity NGF receptor (dissociation constant Kd approximately 10(-9) M). In agreement with this result, the mRNA encoding the low affinity NGF receptor (LNGFR) was detected in ROS 17/2.8 cells, unlike trkA transcripts which encode the high affinity receptor. These data suggest that neurotrophins and their low affinity receptor could play an unsuspected role in bone tissue.

Animals↗