Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,25-dihydroxyvitamin D plays an important role in the regulation of osteoblast gene expression, regulating the expression of bone matrix proteins as well as that of Runx2, a key regulator of osteoblast differentiation. Studies in mice lacking the vitamin D receptor (VDR) have revealed that the actions of the VDR on the skeleton are not required in the setting of normal mineral ion homeostasis. Since paracrine and endocrine factors can compensate for gene defects in vivo, studies were performed to determine whether ablation of the VDR alters the program of osteoblast differentiation in vitro. Studies in primary calvarial cultures revealed that ablation of the VDR enhanced osteoblast differentiation. The cells from the VDR null mice exhibited an earlier onset and increased magnitude of alkaline phosphatase activity, as well as an earlier and sustained increase in mineralized matrix formation, demonstrating that this enhancement persists throughout the program of osteoblast differentiation. The expression of bone sialoprotein, which enhances mineralization, was also increased in the VDR null cultures. To determine whether the increase in osteoblast differentiation was associated with an increase in the number of osteogenic progenitors, the number of osteoblastic colony forming units (CFU-OB) was evaluated. There was a twofold increase in the number of CFU-OB in the cultures isolated from the VDR null mice. Furthermore, the VDR null CFU-OB demonstrated an earlier onset and higher magnitude of expression of alkaline phosphatase activity when compared to the CFU-OB from their wild-type control littermates. These studies demonstrate that the VDR attenuates osteoblast differentiation in vitro and suggest that other endocrine and paracrine factors modulate the effect of the VDR on osteoblast differentiation in vivo.
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PMID:Osteoblasts lacking the vitamin D receptor display enhanced osteogenic potential in vitro. 1551 98

Ca2+ uptake and Ca2+ extrusion mechanisms were studied in enterocytes with different degree of differentiation from chicks adapted to a low Ca2+ diet as compared to animals fed a normal diet. Chicks adapted to a low Ca2+ diet presented hypocalcemia, hypophosphatemia and increased serum 1,25(OH)2D3 and Ca2+ absorption. Low Ca2+ diet increased the alkaline phosphatase (AP) activity, independently of the cellular maturation, but it did not alter gamma-glutamyl-transpeptidase activity. Ca2+ uptake, Ca2+-ATPase and Na(+)/Ca2+ exchanger activities and expressions were increased by the mineral-deficient diet either in mature or immature enterocytes. Western blots analysis shows that vitamin D receptor (VDR) expression was much higher in crypt cells than in mature cells. Low Ca2+ diet decreased the number of vitamin D receptor units in both kinds of cells. In conclusion, changes in Ca2+ uptake and Ca2+ extrusion mechanisms in the enterocytes by a low Ca2+ diet appear to be a result of enhanced serum levels of 1,25(OH)2D3, which would promote cellular differentiation producing cells more efficient to express vitamin D dependent genes required for Ca2+ absorption.
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PMID:Dietary calcium deficiency increases Ca2+ uptake and Ca2+ extrusion mechanisms in chick enterocytes. 1552 61

Physiological actions of osteoblasts are disordered by gravity unloading. We investigated the possibility that the appropriate level of hypergravity could improve osteoblast functions that are susceptible to mechanical unloading. We evaluated hypergravity effects on the 1alpha,25-dihydroxyvitamin D(3) (VD)-inducible osteocalcin expression of primary rat osteoblasts. Cell culture plates were centrifuged for 24 h at 3, 6, 12, 24, and 48 g in a 37 degrees C incubator. The mRNA levels were analyzed by quantitative RT-PCR. The mRNA levels for osteocalcin and vitamin D receptor (VD-R) at 12 g were enhanced to 187% and 228% of the 1 g control, respectively. However, the excess hypergravity conversely decreased osteocalcin expression. Osteocalcin gene expression was enhanced by VD/VD-R through the vitamin D-responsive element in the promoter. The increased osteocalcin expression might reflect the augmented VD-R expression. Alternatively, Runx2, a master gene of osteoblast differentiation, might be responsible for the osteocalcin induction, since the Runx2 mRNA levels were also increased to 247% of control at 12 g. Another VD-inducible osteoblast phenotype, alkaline phosphatase, was also upregulated at 12 g and 24 g. The appropriate level of hypergravity enhanced the VD-inducible expression of osteocalcin, a typical phenotype of osteoblast differentiation. These data suggest molecular features to prevent disuse bone atrophy of long-term bed-rest patients.
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PMID:Hypergravity stimulates osteoblast phenotype expression: a therapeutic hint for disuse bone atrophy. 1565 93

Vitamin D plays a major role in the regulation of mineral homeostasis and affects bone metabolism. So far, detailed knowledge on the vitamin D endocrine system in human bone cells is limited. Here we investigated the direct effects of 1alpha,25-(OH)2D3 on osteoblast differentiation and mineralization. Also, we studied the impact of 24-hydroxylation, generally considered as the first step in the degradation pathway of vitamin D, as well as the role of the nuclear and presumed membrane vitamin D receptor (VDR). For this we used a human osteoblast cell line (SV-HFO) that has the potency to differentiate during culture forming a mineralized extracellular matrix in a 3-week period. Transcriptional analyses demonstrated that both 1alpha,25-(OH)2D3 and the 24-hydroxylated metabolites 24R,25-(OH)2D3 and 1alpha,24R,25-(OH)3D3 induced gene transcription. All metabolites dose-dependently increased alkaline phosphatase (ALP) activity and osteocalcin (OC) production (protein and RNA), and directly enhanced mineralization. 1Alpha,24R,25-(OH)3D3 stimulated ALP activity and OC production most potently, while for mineralization it was equipotent to 1alpha,25-(OH)2D3. The nuclear VDR antagonist ZK159222 almost completely blocked the effects of all metabolites. Interestingly, 1beta,25-(OH)2D3, an inhibitor of membrane effects of 1alpha,25-(OH)2D3 in the intestine, induced gene transcription and increased ALP activity, OC expression and mineralization. In conclusion, not only 1alpha,25-(OH)2D3, but also the presumed 24-hydroxylated "degradation" products stimulate differentiation of human osteoblasts. 1Alpha,25-(OH)2D3 as well as the 24-hydroxylated metabolites directly enhance mineralization, with the nuclear VDR playing a central role. The intestinal antagonist 1beta,25-(OH)2D3 acts in bone as an agonist and directly stimulates mineralization in a nuclear VDR-dependent way.
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PMID:Evidence that both 1alpha,25-dihydroxyvitamin D3 and 24-hydroxylated D3 enhance human osteoblast differentiation and mineralization. 1674 65

Bone disease is an important complication among very low birth weight (VLBW, <1500 g) infants. In adults, osteoporosis is associated with polymorphisms of vitamin D receptor (VDR), estrogen receptor (ER), and collagen Ialpha1 (COLIA1) genes. However, limited information is available regarding the role of these polymorphisms in bone disease in premature infants. We have investigated the possible association between bone disease and the allelic polymorphisms of these three genes in 65 VLBW infants. Twenty infants (30.8%) were diagnosed with bone disease based on high activity of bone formation (serum alkaline phosphatase and osteocalcin), bone resorption (urinary excretion of calcium and pyridinium crosslink) markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA)(n)] allelic variant of ER gene and bone disease was observed. Infants without bone disorder more often carried a high number of repeats [(TA)(n) >18] [odds ratio (OR): 0.17, 95% confidence interval (CI): 0.05-0.55]. A low number of repeats [(TA)(n) <19] was found more frequently in infants suffering from bone disease (OR: 6.00, 95% CI: 1.77-20.31). Significant interaction (p = 0.009) between VDR and COLIA1 genotypes was observed. In a logistic regression model, bone disorder of preterms significantly correlated with male gender (p = 0.002), lower gestational age (p = 0.015), homozygous allelic variants of high number of (TA)(n) repeats (p = 0.006), and interaction between VDR and COLIA1 genotype (p = 0.009).
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PMID:Influence of genetic polymorphisms on bone disease of preterm infants. 1698 90

black triangle An oral formulation of paricalcitol has been developed for the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease.black triangle Paricalcitol is a synthetic vitamin D analog that binds to the vitamin D receptor inducing suppression of parathyroid hormone (PTH) secretion.black triangle Oral paricalcitol was significantly more effective than placebo in treating secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. In a pooled analysis of three well designed, 24-week trials, two consecutive reductions from baseline in intact PTH levels of >/=30% were achieved by significantly more paricalcitol than placebo recipients (91% vs 13%).black triangle In addition, mean levels of the biochemical bone markers serum bone-specific alkaline phosphatase, serum osteocalcin, and urinary pyridinoline were reduced from baseline to a significantly greater extent with paricalcitol than with placebo, indicating a reduction in bone turnover.black triangle Oral paricalcitol was well tolerated; there was no significant difference between paricalcitol and placebo recipients in the incidence of hypercalcemia, hyperphosphatemia, or elevated calcium-phosphorus product.
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PMID:Oral paricalcitol. 1700 90

Of the various risk factors contributing to osteoporosis, dietary/lifestyle factors are important. In a clinical study we reported that women with caffeine intakes >300 mg/day had higher bone loss and women with vitamin D receptor (VDR) variant, tt were at a greater risk for this deleterious effect of caffeine. However, the mechanism of how caffeine effects bone metabolism is not clear. 1,25-Dihydroxy vitamin D(3) (1,25(OH)(2)D(3)) plays a critical role in regulating bone metabolism. The receptor for 1,25(OH)(2)D(3), VDR has been demonstrated in osteoblast cells and it belongs to the superfamily of nuclear hormone receptors. To understand the molecular mechanism of the role of caffeine in relation to bone, we tested the effect of caffeine on VDR expression and 1,25(OH)(2)D(3) mediated actions in bone. We therefore examined the effect of different doses of caffeine (0.2, 0.5, 1.0 and 10mM) on 1,25(OH)(2)D(3) induced VDR protein expression in human osteoblast cells. We also tested the effect of different doses of caffeine on 1,25(OH)(2)D(3) induced alkaline phosphatase (ALP) activity, a widely used marker of osteoblastic activity. Caffeine dose dependently decreased the 1,25(OH)(2)D(3) induced VDR expression and at concentrations of 1 and 10mM, VDR expression was decreased by about 50-70%, respectively. In addition, the 1,25(OH)(2)D(3) induced alkaline phosphatase activity was also reduced at similar doses thus affecting the osteoblastic function. The basal ALP activity was not affected with increasing doses of caffeine. Overall, our results suggest that caffeine affects 1,25(OH)(2)D(3) stimulated VDR protein expression and 1,25(OH)(2)D(3) mediated actions in human osteoblast cells.
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PMID:Caffeine decreases vitamin D receptor protein expression and 1,25(OH)2D3 stimulated alkaline phosphatase activity in human osteoblast cells. 1722 52

The Wnt pathway regulates cell proliferation and differentiation in development and disease, with a number of recent reports linking Wnt to control of osteoblast differentiation and bone mass. There is also accumulating evidence for interaction between the Wnt and nuclear receptor (NR)-mediated control pathways in non-osseous tissues. Calcitriol (1,25D(3)), which is the active hormonal ligand for the vitamin D receptor (VDR), a member of the NR superfamily, induces osteoblastic cell cycle arrest and expression of genes involved in matrix mineralization in vitro, with over-expression of VDR in mature osteoblasts increasing bone mass in mice. To determine whether the vitamin D and Wnt control pathways interact in osteoblastic regulation, we investigated the treatment effects of 1,25D(3) and/or lithium chloride (LiCl), which mimics canonical Wnt pathway activation, on osteoblast proliferation and differentiation. Treatments were initiated at various stages in differentiating cultures of the MC3T3-E1 osteoprogenitor cell line. Treatment of subconfluent cultures (day 1) with either agent transiently increased cell proliferation but decreased viable cell number, with additive inhibition after combined treatment. Interestingly, although early response patterns of alkaline phosphatase activity to 1,25D(3) and LiCl were opposite, mineralized nodule formation was virtually abolished by either treatment initiated at day 1 and remained very low after initiating treatments at matrix-formation stage (day 6). By contrast, mineralized nodule formation was substantial but reduced if 1,25D(3) and/or LiCl treatment was initiated at mineralization onset (day 13). Osteocalcin production was reduced by all treatments at all time points. Thus, vitamin D and/or canonical Wnt pathway activation markedly reduced mineralization, with additive inhibitory effects on viable cell number. The strength of the response was dependent on the stage of differentiation at treatment initiation. Importantly, the inhibitory effect of LiCl in this committed osteoblastic cell line contrasts with the stimulatory effects of genetic Wnt pathway activation in human and mouse bone tissue. This is consistent with the anabolic Wnt response occurring at a stage prior to the mature osteoprogenitor in the intact skeleton and suggests that prolonged or repeated activation of the canonical Wnt response in committed cells may have an inhibitory effect on osteoblast differentiation and function.
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PMID:Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation. 1751 86

The 1,25 dihydroxyvitamin D3 [1,25(OH)2D3]-induced differentiation of osteoblasts comprises the sequential induction of cell cycle arrest at G0/G1 and the expression of bone matrix proteins. Reports differ on the effects of IGF binding protein (IGFBP)-5 on bone cell growth and osteoblastic function. IGFBP-5 can be growth stimulatory or inhibitory and can enhance or impair osteoblast function. In previous studies, we have shown that IGFBP-5 localizes to the nucleus and interacts with the retinoid receptors. We now show that IGFBP-5 interacts with nuclear vitamin D receptor (VDR) and blocks retinoid X receptor (RXR):VDR heterodimerization. VDR and IGFBP-5 were shown to colocalize to the nuclei of MG-63 and U2-OS cells and coimmunoprecipitate in nuclear extracts from these cells. Induction of osteocalcin promoter activity and alkaline phosphatase activity by 1,25(OH)2D3 were significantly enhanced when IGFBP-5 was down-regulated in U2-OS cells. Moreover, we found IGFBP-5 increased basal alkaline phosphatase activity and collagen alpha1 type 1 expression, and that 1,25(OH)2D3 was unable to further induce the expression of these bone differentiation markers in MG-63 cells. Expression of IGFBP-5 inhibited MG-63 cell growth and caused cell cycle arrest at G0/G1 and G2/M. Furthermore, IGFBP-5 reduced the effects of 1,25(OH)2D3 in blocking cell cycle progression at G0/G1 and decreased the expression of cyclin D1. These results demonstrate that IGFBP-5 can interact with VDR to prevent RXR:VDR heterodimerization and suggest that IGFBP-5 may attenuate the 1,25(OH)2D3-induced expression of bone differentiation markers while having a modest effect on the 1,25(OH)2D3-mediated inhibition of cell cycle progression in bone cells.
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PMID:Insulin-like growth factor binding protein-5 interacts with the vitamin D receptor and modulates the vitamin D response in osteoblasts. 1759 20

Calcitriol-resistant rickets (CRR) is an autosomal recessive disease due to a defect in the vitamin D receptor (VDR) or a site distal to it. The main characteristics are extreme rickets, with growth attenuation, osteomalacia, secondary hyperparathyroidism, severe dental caries, and alopecia. Serum studies reveal hypocalcemia, hypophosphatemia, very high calcitriol, and increased alkaline phosphatase levels. The clinical and chemical abnormalities do not respond to therapy with high-dose vitamin D, indicating target organ unresponsiveness. Eleven different mutations in the gene-encoding VDR have thus far been reported. They affect either the C-terminal ligand-binding region or the N-terminal DNA binding zinc-fingers sequences, with mutation hot spots identified at conserved sequences among the steroid-thyroid receptors superfamily. These result in impaired calcitriol binding to target organs, signified in vitro as failure of fibroblasts to bind [(3)H]calcitriol or to respond to calcitriol by 24-hydroxylase activity enhancement. Receptor studies and mutational analyses are used for prenatal diagnosis of CRR. Therapy with high-dose calcium overcomes the VDR defect, normalizes serum calcium, and maintains bone remodeling and mineral apposition. These responses to therapy have interesting implications upon our understanding of the potential role of calcium alone and that of vitamin D in bone physiology. Like other hormone-resistant diseases, CRR, with its various mutations, provides the opportunity for investigating the nature of vitamin D and of VDR physiology, which has been only partially explored to date.
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PMID:Calcitriol-resistant rickets due to vitamin D receptor defects. 1840 5


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