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A Dusso

Publications and source records attributed to A Dusso.

At least 19 recordsLinked to original sources
PubMed2004

1alpha-Hydroxylase transactivation by gamma-interferon in murine macrophages requires enhanced C/EBPbeta expression and activation.

gamma-Interferon [gamma-IFN] induction of macrophage 1alpha-hydroxylase mRNA and activity causes severe hypercalcemia in granulomatous disorders. These studies demonstrate transcriptional regulation. gamma-IFN induces the activity of the murine 1alpha-hydroxylase [-1651; +22] promoter in the murine macrophage cell line Raw 264.7 only after a 24h exposure. This slow kinetics is incompatible with classical gamma-IFN-mediated transactivation. In fact, gamma-IFN response mapped to the minimal [-85; +11] promoter, which lacks GAS or ISRE sites but contains a putative C/EBPbeta site. C/EBPbeta is a gamma-IFN inducible gene and a novel mediator of gamma-IFN-regulated transcription. As expected for a C/EBPbeta-driven transcription, ectopic C/EBPbeta expression was sufficient to increase 1alpha-hydroxylase activity, enhance minimal promoter activity and potentiate the induction of this promoter by gamma-IFN. Importantly, the dominant negative C/EBPbeta isoform antagonized C/EBPbeta-transcriptional activity. gamma-IFN induction of C/EBPbeta expression is not sufficient for gamma-IFN induction of minimal promoter activity. There is also a cell-specific induction of C/EBPbeta-transcriptional activity by gamma-IFN. In Raw cells, specific inhibition of gamma-IFN induction of endogenous-C/EBPbeta phosphorylation by MEKK1 markedly reduced basal promoter activity and the response to gamma-IFN. We conclude that gamma-IFN-induction of C/EBPbeta expression and activation by phosphorylation contributes to gamma-IFN-transcriptional control of 1alpha-hydroxylase expression in murine macrophages.

Animals↗
PubMed2001

Role of phosphorus in the pathogenesis of secondary hyperparathyroidism.

Secondary hyperparathyroidism (SH) and hyperplasia of the parathyroid glands (PTG) are universal complications in patients with CRF. In early renal failure, reduction in serum calcitriol and moderate decreases in ionized calcium contribute to greater synthesis and secretion of PTH. As renal disease progresses, a reduction in parathyroid expression of vitamin D receptor and calcium receptor renders the PTG more resistant to both calcitriol and calcium. High dietary phosphorus (P), independent of calcium and calcitriol, further enhances uremia-induced PTG hyperplasia and PTH synthesis and secretion, the latter by posttranscriptional mechanisms. Once SH develops, dietary P restriction can return the high serum PTH levels toward normal, however, parathyroid hyperplasia persists. Studies in our laboratory identified 2 of the mechanisms involved in the opposing effects of high and low dietary P content on PTG growth. Whereas high dietary P increases parathyroid expression of transforming growth factor alpha (TGFalpha), a growth promoter, P restriction induces the cyclin-dependent kinase inhibitor p21, an inducer of growth arrest. Both effects of P are specific for the PTG. No increase in either protein was observed in liver or intestine. TGFalpha induction of hyperplasia involves binding to the epidermal growth factor receptor and activation of mitogen activated protein (MAP) kinases cascades. p21 blocks progression through the cycle and cell division by inactivating cyclin/cyclin-dependent kinase complexes. Preventing hyperphosphatemia and elevated Ca x P product in renal failure not only ameliorates the progression of SH and bone disease but also the morbidity and mortality resulting from vascular calcification.

Animals↗
PubMed2000

A novel mechanism for skeletal resistance in uremia.

BACKGROUND: In treating secondary hyperparathyroidism, the target level of serum intact parathyroid hormone (I-PTH) should be three to five times normal to prevent adynamic bone disease. In circulation, there is a non-(1-84) PTH-truncated fragment, likely 7-84, which, in addition to PTH 1-84, is measured by most I-PTH immunoradiometric (IRMA) assays, giving 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 PTH molecule. METHODS: Using this new IRMA assay (Whole PTH) and the Nichols "intact" PTH assay, we compared the ability of each assay to recognize human PTH (hPTH) 1-84 and hPTH 7-84 and examined the percentage of non-1-84 PTH in circulation and in parathyroid glands. Possible antagonistic effects of the 7-84 PTH fragment on the biological activity of 1-84 PTH in rats were also tested. RESULTS: In 28 uremic patients, PTH values measured with the Nichols assay, representing a combined measurement of both hPTH 1-84 and hPTH 7-84, were 34% higher than with the Whole assay (hPTH 1-84 only); the median PTH was 523 versus 318 pg/mL (P < 0.001). Similar results were found in 14 renal transplant patients. In osteoblast-like cells, ROS 17.2, 1-84 PTH (10-8 mol/L) increased cAMP from 18.1 +/- 1.25 to 738 +/- 4.13 mmol/well. Conversely, the same concentration of 7-84 PTH had no effect. In parathyroidectomized rats fed a calcium-deficient diet, 7-84 PTH was not only biologically inactive, but had antagonistic effects on 1-84 PTH in bone. Plasma calcium was increased (0.65 mg/dL) two hours after 1-84 PTH treatment, while 7-84 PTH had no effect. When 1-84 PTH and 7-84 PTH were given simultaneously in a 1:1 molar ratio, the calcemic response to 1-84 PTH was decreased by 94%. In normal rats, the administration of 1-84 PTH increased renal fractional excretion of phosphate (11.9 to 27.7%, P < 0.001). However, when 1-84 PTH and 7-84 PTH were given simultaneously, the 7-84 PTH decreased the phosphaturic response by 50.2% (P < 0.005). Finally, in surgically excised parathyroid glands from six uremic patients, we found that 44.1% of the total intracellular PTH was the non-PTH (1-84), most likely PTH 7-84. CONCLUSION: In patients with chronic renal failure, the presence of high circulating levels of non-1-84 PTH fragments (most likely 7-84 PTH) detected by the "intact" assay and the antagonistic effects of 7-84 PTH on the biological activity of 1-84 PTH explain the need of higher levels of "intact" PTH to prevent adynamic bone disease.

Animals↗
PubMed1999

Pathogenesis of secondary hyperparathyroidism.

Secondary hyperparathyroidism is a universal complication in patients with chronic renal failure. Hyperplasia of the parathyroid glands is typically seen in these patients. In early renal failure, alteration in vitamin metabolism, decreased levels of calcitriol and moderate decreases in ionized calcium may allow greater synthesis and secretion of PTH. As the disease progresses, there is a decrease in the number of vitamin D receptors (VDR) and calcium receptors (CaR). The decreased number of VDR and CaR makes the parathyroid glands more resistant to calcitriol and calcium. Phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol, and by a post-transcriptional mechanism increases PTH synthesis and secretion. Experimental work in uremic rats demonstrated that if the animals are fed a high-phosphorus diet, they not only developed secondary hyperparathyroidism but parathyroid cell hyperplasia. If the diet is then reduced in phosphorus, the levels of PTH return to normal. However, the parathyroid cell hyperplasia persists and no apoptosis is seen. Thus, the control of the three most important factors, calcium, calcitriol and phosphorus, is critical to prevent the development of secondary hyperparathyroidism and hyperplasia of the parathyroid glands.

Animals↗
PubMed1999

New analogs of vitamin D3.

Calcitriol, the most active metabolite of vitamin D, controls parathyroid gland growth and suppresses the synthesis and secretion of parathyroid hormone (PTH). However, because of its potent effects on intestinal calcium absorption and bone mobilization, calcitriol treatment can induce hypercalcemia, often precluding its use at therapeutic doses. Hyperphosphatemia is also a persistent problem among patients undergoing chronic hemodialysis and can be aggravated by therapeutic doses of calcitriol. Several pharmaceutical companies were able to modify the side-chain of the 1,25(OH)2D3, allowing some of these new analogs to retain the action on the parathyroid glands while decreasing their hypercalcemic and hyperphosphatemic effects. The structure-activity relationship for ligand-mediated transcriptional regulation has been studied in detail. In some analogs the serum binding protein (DBP) plays a key role in determining the pharmacokinetics of the vitamin D compound. The affinity to DBP for 22-oxacalcitriol (OCT), an analog of calcitriol for the treatment of secondary hyperparathryoidism, is approximately 300-400 times lower than that of calcitriol and the analog is rapidly cleared from the circulation. The mechanisms for the selectivity of 19-nor-1,25(OH)2D2 (paricalcitol) (Zemplar) another analog of calcitriol, is clearly different from OCT. Although the mechanisms of action is not completely known, it does appear that paricalcitol down-regulates the VDR in the intestine. It is likely that the unique biological profiles of vitamin D analogs in vivo are due to multiple mechanisms. Understanding the molecular basis of the analog selectivity will not only provide an explanation for their unique actions but allow intelligent design of more effective analogs in the future.

Animals↗
PubMed1999

The role of phosphorus in the development of secondary hyperparathyroidism and parathyroid cell proliferation in chronic renal failure.

Hyperplasia of the parathyroid glands and high levels of parathyroid hormone (PTH) are among the most consistent findings in patients with chronic renal failure. In early renal failure, alterations in vitamin D metabolism play a key role in the development of secondary hyperparathyroidism. Low levels of calcitriol and decreased expression of the vitamin D responsive element may allow greater synthesis and secretion of PTH. Phosphorus independent of serum calcium and calcitriol increases PTH synthesis and secretion by a post-transcriptional mechanism. Studies in vivo in uremic rats demonstrated that an increase in dietary phosphorus induces parathyroid gland hyperplasia. If the rats are then fed a low-phosphorus diet, the levels of serum PTH return to normal; however, the size of the parathyroid glands remains enlarged. No apoptosis was observed in the glands. To further characterize the effects of phosphorus on PTH synthesis and secretion, intact rat parathyroid glands were metabolically labeled during a 4-hour incubation in methionine-free medium containing 1.25 mM Ca2+, [35S]methionine, and either 2.8 mM or 0.2 mM phosphorus. Total PTH secretion, as measured in the medium, was increased more than 6-fold in glands incubated in high-phosphorus medium compared with glands incubated in the low-phosphorus medium. Thus, in the past 20 years, numerous investigators have provided strong evidence for the action of phosphorus on PTH secretion. Unfortunately, the absence of a parathyroid cell line is slowing the progress in understanding the molecular mechanism(s) involved in phosphorus regulation of PTH.

Animals↗
PubMed1999

Vitamin D.

The vitamin D endocrine systems plays a critical role in calcium and phosphate homeostasis. The active form of vitamin D, 1, 25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], 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)(2)D(3) also 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)(2)D(3) is the activation of genes that control intestinal calcium transport. However, 1,25(OH)(2)D(3) can 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)(2)D(3) and its analogs.

Animals↗
PubMed1996

Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.

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)2D3, whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH)2D3 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 +/- 25 vs. 35 +/- 3.5 pg/ml, P < 0.01), PTG weight (1.80 +/- 0.13 vs. 0.88 +/- 0.06 microg/gram of body weight, P < 0.01), and PTG DNA (1.63 +/- 0.24 vs. 0.94 +/- 0.07 microg DNA/gland, P < 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)2D3 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 +/- 215 vs. 1,033 +/- 209 pg/microg DNA, P < 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 microg/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)2D3.

Analysis of Variance↗
PubMed1995

Microtubules mediate cellular 25-hydroxyvitamin D3 trafficking and the genomic response to 1,25-dihydroxyvitamin D3 in normal human monocytes.

The genomic actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are mediated by the intracellular vitamin D receptor (VDR). Although immunocytochemistry has shown that disruption of microtubular assembly prevents nuclear access of the sterol-VDR complex, the role of microtubules in the response to 1,25(OH)2D3 has not been studied in viable cells. Our studies examined this interaction in normal human monocytes. Monocytes convert 25(OH)D3 to 1,25(OH)2D3 and to 24-hydroxylated metabolites more polar than 1,25(OH)2D3. Microtubule disruption totally abolished the ability of exogenous 1,25(OH)2D3 to suppress its own synthesis and to induce 24-hydroxylase mRNA and activity, without affecting either total 1,25(OH)2D3 uptake or maximal 1,25(OH)2D3-VDR binding. Thus, intact microtubules are essential for 1,25(OH)2D3-dependent modulation of gene transcription. Interestingly, microtubule disruption also decreased monocyte 1,25(OH)2D3 synthesis, not by decreasing the Vmax of monocyte mitochondrial 1 alpha-hydroxylase but through an increase in the Km for 25(OH)2D3. We examined 25(OH)D3 transport. Microtubule disruption did not affect total cellular 25(OH)D3 uptake but reduced its intracellular trafficking to the mitochondria. Thus, microtubules participate in intracellular 25(OH)D3 transport, and their integrity determines normal 1,25(OH)2D3 synthesis.

Biological Transport↗
PubMed1995

Kinetics of monocyte 1 alpha-hydroxylase in renal failure.

In chronic uremia, the requirement of supraphysiological doses of serum 25-hydroxyvitamin D3 [25(OH)D3] for the normalization of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels has been attributed to impaired substrate availability to renal 1 alpha-hydroxylase. Because serum 1,25(OH)2D3 can also be corrected by 25(OH)D3 supplementation in bilaterally nephrectomized patients, we examined the role of substrate availability on 1,25(OH)2D3 production by peripheral blood monocytes (PBM). In hemodialysis patients (HP), 25(OH)D3 uptake was 50% lower than normal, and the maximal velocity (Vmax) and apparent Michaelis constant (Km) for 25(OH)D3 of 1 alpha-hydroxylase were 2.7- and 4-fold above normal, respectively. When serum 1,25(OH)2D3 of HP was corrected by intravenous 1,25(OH)2D3, 25(OH)D3 uptake, Km, and Vmax returned to normal values. The effect of 25(OH)D3 supplementation was also examined. In normal adults, 25(OH)D3 administration had no effect on serum 1,25(OH)2D3 levels nor on the Km or the Vmax of PBM 1 alpha-hydroxylase but caused a 11-fold increase in serum 24R,25-dihydroxyvitamin D3[24R, 25(OH)2D3]. In HP, 25(OH)D3 therapy raised serum 1,25(OH)2D3 and reduced the Km and Vmax of PBM 1 alpha-hydroxylase, which correlated negatively with serum 1,25(OH)2D3. However, serum 24R,25(OH)2D3 only increased slightly above basal. These results demonstrate that, in HP, 1) impaired uptake of 25(OH)D3 and low affinity for substrate determine the need for high 25(OH)D3 levels to normalize serum 1,25(OH)2D3, despite higher enzymatic activity; 2) 1,25(OH)2D3 deficiency plays a role in enhanced 1,25(OH)2D3 synthesis and impaired access of 25(OH)D3 to PBM 1 alpha hydroxylase; and 3) abnormal 25(OH)D3 delivery also affects 24-hydroxylation.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1994

Extrarenal production of calcitriol.

Similar to the discovery of the VDR in nonclassical target tissues, the expression of 1 alpha-hydroxylase activity in immune cells, in the hematopoietic system, in tissues at early stages in development, in keratinocytes, and in the liver raises numerous questions about the physiological role of endogenous 1,25(OH)2D3 production. Extrarenal sources are regulated independently from the renal enzyme. The tight control of nonrenal 1 alpha-hydroxylase by physiological levels of calcitriol under normal circumstances and the total absence of regulation in several pathological states are consistent with 1,25(OH)2D3 synthesis having a local role rather than contributing to systemic calcitriol homeostasis. The simultaneous expression of vitamin D receptors, constitutive 1 alpha-hydroxylase, and inducible 24-hydroxylase activity in the same cell or in cells of the nearby environment suggests that they constitute a means for an in situ regulation of the response to vitamin D. Experimental evidence indicates that tissue-specific vitamin D microendocrine systems participate in transmural calcium transport, in normalizing serum calcitriol in chronic renal failure, in the control of hematopoiesis, in the modulation of the immune response, and in cellular growth and differentiation in a variety of cell types. A complete understanding of the physiological relevance of extrarenal calcitriol synthesis awaits cloning of the 1 alpha-hydroxylase and characterization of the molecular mechanisms modulating its expression.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1993

Lower affinity for substrate for extrarenal synthesis of calcitriol in chronic uremia.

Previous studies from our laboratory have shown that anephric patients have very low, but detectable, levels of 1,25(OH)2D3 (calcitriol) that can be increased to normal by administration of large doses of 25(OH)D3. The report of 1 alpha-hydroxylase activity in pig liver with an affinity for substrate significantly lower than that of the renal enzyme, led us to use the rat as an experimental model to further clarify the need of supraphysiological levels of 25(OH)D3 to correct calcitriol deficiency in chronic uremia. We have measured 1,25(OH)2D3 production by rat liver. Cytosol free liver homogenates (CFH) from normal rats were incubated with 25(OH)D3 and the production of 1,25(OH)2D3 was measured using the thymus radioreceptor assay after solid phase C18 extraction and HPLC purification of the samples. 1,25(OH)2D3 production was linear up to 30 minutes and a CFH protein concentration up to 20 mg. Saturability was attained for a substrate concentration of approximately 60 microM. Ketoconazole, a cytochrome P450 inhibitor, blocked calcitriol production in a dose dependent fashion. Total inhibition of the liver 1 alpha-hydroxylase was achieved with 180 microM ketoconazole. We next compared the kinetics of the 1 alpha-hydroxylases of normal and uremic rat livers. Maximal velocities were not statistically different (139.6 +/- 22.3 pg/mg/min for normals and 217.1 +/- 73.3 pg/mg/min for uremic rats). However, the apparent Km was 35.9 +/- 3.2 microM for uremic animals, significantly higher (P < or = 0.001) than that of normal rats (16.6 +/- 0.7 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1993

Differential catabolism of 22-oxacalcitriol and 1,25-dihydroxyvitamin D3 by normal human peripheral monocytes.

22-Oxacalcitriol [1,25-(OH)2-22oxa-D3] mimics the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in a variety of target tissues, including the systemic control of calcitriol metabolism. Similar to 1,25-(OH)2D3, 1,25-(OH)2-22oxa-D3 decreases the rate of 1,25-(OH)2D3 synthesis and accelerates its metabolic clearance rate. We have previously shown that in normal human monocytes, physiological concentrations of 1,25-(OH)2D3 and 1,25-(OH)2-22oxa-D3 determine identical suppression of 1,25-(OH)2D3 synthesis. Moreover, both sterols have a similar potency to induce vitamin D degradation through stimulation of the C24-hydroxylation pathway. In this study, we examined the ability of normal human monocytes to metabolize 1,25-(OH)2-22oxa-D3 and whether the enzymes involved are the same as those that catabolize 1,25-(OH)2D3. Time-course experiments demonstrated no detectable basal catabolic activity. However, exogenous 1,25-(OH)2D3 at physiological concentrations induced 1,25-(OH)2-22oxa-D3 degradation by normal human monocytes. Competition experiments showed that a 10-fold molar excess of unlabeled 1,25-(OH)2D3 inhibited tritiated-1,25-(OH)2-22oxa-D3 catabolism by 85%, whereas a 10-fold excess of unlabeled 1,25-(OH)2-22oxa-D3 reduced tritiated-1,25-(OH)2-22oxa-D3 catabolism by 33%. In contrast, although a 10-fold excess of unlabeled 1,25-(OH)2D3 reduced tritiated 1,25-(OH)2D3 catabolism by 60%, a 1000-fold excess of 1,25-(OH)2-22oxa-D3 was required to reduce tritiated 1,25-(OH)2D3 catabolism to this degree. The apparent Km for 1,25-(OH)2-22oxa-D3 was significantly higher than that of 1,25-(OH)2D3 (2.0 +/- 0.8 0.9 +/- 0.2 nM, respectively; P < 0.001) for the catabolic pathway induced by physiological concentrations of 1,25-(OH)2D3. Moreover, the presence of 0.65 nM 1,25-(OH)2D3 caused an additional increase in the Km for 1,25-(OH)2-22oxa-D3 (3.2 +/- 0.8 nM). These data suggest that 1,25-(OH)2-22oxa-D3 may be less accessible than 1,25-(OH)2D3 to the hydroxylases involved in vitamin D catabolism. The resulting prolonged biological half-life of the analog in certain target tissues may be involved in its selectivity.

Binding, Competitive↗
PubMed1992

22-oxacalcitriol suppresses 25-hydroxycholecalciferol-1 alpha-hydroxylase in rat kidney.

22-oxacalcitriol can decrease the serum level of 1,25-dihydroxycholecalciferol by increasing its metabolic clearance rate and decreasing its production rate. To determine whether 22-oxacalcitriol suppressed the renal 25-hydroxycholecalciferol-1 alpha- hydroxylase we treated rats with 200 ng of 22-oxacalcitriol daily for 1 week. Enzyme activity was measured in vitro by measurement of production of 1,25-dihydroxycholecalciferol by renal slices incubated with 25-hydroxycholecalciferol. 22-oxacalcitriol significantly decreased the 25-hydroxycholecalciferol-1 alpha-hydroxylase activity from 797 +/- 208 pg of 1,25-dihydroxycholecalciferol/g of kidney/h in the control group to 257 +/- 150 pg of 1,25-dihydroxycholecalciferol/g of kidney/h (p less than 0.05). This is the first demonstration of suppression of the renal 25-hydroxycholecalciferol-1 alpha-hydroxylase by the vitamin D3 analog, 22-oxacalcitriol.

Animals↗
PubMed1990

New active analogues of vitamin D with low calcemic activity.

In conclusion, a number vitamin D analogues have been developed that have very low calcemic activity but retain several other properties of 1,25-(OH)2D3, including the ability to differentiate leukemia and skin cells, to enhance the immune response, and to suppress parathyroid hormone levels. Although the mechanism of this selective activity is not yet clear, these analogues may provide new insights into the differences in action of 1,25-(OH)2D3 in various target tissues. Most importantly, the selective action of these analogues may be exploited for the treatment of diseases such as leukemia, psoriasis and hyperparathyroidism.

Animals↗