Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a novel polymerase chain reaction (PCR) and deoxyribonucleic acid (DNA) sequencingbased assay for rapid genotyping of the polymorphic Sp1 binding site in the COL1A1 gene (1). A single nucleotide G-->T substitution polymorphism at this GC-rich site has recently been reported to be a predictive genetic marker for low bone mineral density (BMD). To simplify screening for this marker, we optimized PCR conditions and subjected the amplicons to pyrosequencing, which is a convenient high-throughput sequence analysis technique, readily amenable to automation. The analysis of 200 deidentified convenience DNA samples extracted from blood revealed genotype frequences in Hardy-Weinberg equilibrium (SS 68.0%, Ss 28.5%, and ss 3.5%) in agreement with other studies of European populations. This study demonstrates for the first time that pyrosequencing can be used for rapid identification of the osteoporosis-associated single nucleotide polymorphism (SNP) in the COL1A1 gene.
Mol Biotechnol 2004 Jan
PMID:Rapid genotyping of the osteoporosis-associated polymorphic transcription factor Sp1 binding site in the COL1A1 gene by pyrosequencing. 1473 26

Pretreatment with 1 nM 1,25-dihydroxyvitamin D(3) (1,25), or non-hypercalcemic Vitamin D analogs, upregulated the response of creatine kinase (CK) to 17beta-estradiol (30 nM E(2)), raloxifene (3000 nM RAL) or dihydrotestosterone (300 nM DHT) in primary human bone cells. Previously, we reported that these osteoblast-like cells responded to gonadal steroids in a sex specific manner. Bone cells derived from pre-menopausal women showed greater stimulation of CK specific activity by E(2) than bone cells from post-menopausal women; in male-derived cells no age related difference was found. In this study, we treated cells derived from female or male bones, at different ages, with the side chain modified analogs of Vitamin D: CB 1093 (CB), EB 1089 (EB), MC 1288 (MC) and the demonstrably non-calcemic hybrid analog JK 1624 F2-2 (JKF), by daily addition of 1 nM, for 3 days. On day 4, cells were incubated with sex steroids for 4h and cell extracts were prepared. Pretreatment with JKF or CB significantly upregulated the response to 30 nM E(2) in all female-derived cells and to 300 nM DHT in mature male-derived cells. In cells from older males, only JKF caused augmentation of DHT action. Bone cells from pre- or post-menopausal females responded to 3000 nM RAL by increased CK activity to the same extent as to 30 nM E(2); however, RAL and E(2), when applied together, resulted in mutual annihilation of their agonist activities. Vitamin D analogs prevented the antagonistic effect of RAL in the presence of E(2), possibly due to increased numbers of ERs. Both estrogen receptors, alpha (ERalpha) and beta (ERbeta), were expressed in male- as well as in female-derived cells. However, only in female-derived cells were ERalpha and ERbeta upregulated by pretreatment with Vitamin D analogs. This study raises the possibility of testing combined Vitamin D analog and estrogen replacement treatment for post-menopausal women to prevent osteoporosis.
J Steroid Biochem Mol Biol 2004 Feb
PMID:Treatment with non-hypercalcemic analogs of 1,25-dihydroxyvitamin D3 increases responsiveness to 17beta-estradiol, dihydrotestosterone or raloxifene in primary human osteoblasts. 1508 53

Glucocorticoid use results in an increase risk for fractures. Over the past 10 years, we have a greater understanding of the epidemiology, pathophysiology, prevention and treatment of glucocorticoid induced osteoporosis. This article reviews these recent findings and selective practice guidelines.
J Steroid Biochem Mol Biol 2004 Apr
PMID:The treatment of glucocorticoid-induced osteoporosis. 1514 43

Five analogs of 19-nor-1alpha,25-dihydroxyvitamin D(3) are described that show highly selective and potent activities. The 2-methylene-19-nor-(20S)-1alpha25-dihydroxyvitamin D(3) (2MD) and its 2alpha-methyl sister are selectively active on the osteoblast. 2MD is bone anabolic and causes bone formation in vivo and in vitro and is being developed as a therapy for bone loss diseases such as osteoporosis. 2-Methylene-19-nor (20S)-bishomo-1alpha-hydroxypregnacalciferol (2BMP) has no activity on calcium in vivo while totally suppressing circulating parathyroid hormone. Its homologs, i.e. 2-methylene-19-nor-1alpha-hydroxy-homopregnacalciferol (2MP) and 2-methylene-19-nor-1alpha-hydroxypregnacalciferol (2MPC) act similarly but are either less selective (2MP) or not as potent (2MPC). These abbreviated side chain analogs will be developed for diseases where a rise in serum calcium is not desired, as for example, cancer, renal osteodystrophy, psoriasis and autoimmune diseases.
J Steroid Biochem Mol Biol 2004 May
PMID:Therapeutic potential of the 2-alkyl and 2-alkylidene-19-nor-(20S)-modified analogs of 1alpha,25-dihydroxyvitamin D3. 1522 49

The vdr gene is a candidate for osteoporosis susceptibility, with conflicting results in association studies. We have designed and optimized an individual allele-specific and DNA pooling PCR-based methodology to quantitate BsmI and FokI polymorphisms of the vdr gene and studied single-nucleotide polymorphisms (SNPs) from pooled DNA samples. The allele frequency in DNA pooling experiments has been analyzed by kinetic PCR: quantitative real-time PCR (QRT-PCR). A Spanish cohort of 225 healthy postmenopausal women was studied. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA) and quantitative ultrasound calcaneous densitometry. Allele-specific PCR amplification of BsmI and FokI genes showed full concordance with the PCR-RFLP approach. The prevalence of the three BsmI VDR genotypes was 19.1, 44.9 and 36.0% for BB, Bb and bb, respectively. In the case of the FokI locus, the prevalence of genotypes was 40.4, 48.0 and 11.6% for FF, Ff and ff, respectively. No positive correlation was found between polymorphism and BMD. The DNA pooling procedure was validated. No differences were found in allele frequencies and T-score data obtained using the high throughput DNA pooling approach, as compared to known individual frequencies. In our hands, this is a very useful approach to study quantitative (thus polygenic) traits like osteoporosis susceptibility.
J Steroid Biochem Mol Biol 2004 May
PMID:Allele-frequency determination of BsmI and FokI polymorphisms of the VDR gene by quantitative real-time PCR (QRT-PCR) in pooled genomic DNA samples. 1522 73

Although it was originally proposed that the major role of calbindin is to facilitate the vitamin D dependent movement of calcium through the cytosolic compartment of the intestinal or renal cell, we found that calbindin also has a major role in different cell types in protecting against apoptotic cell death. Calbindin, which buffers calcium, can inhibit apoptosis induced by different proapoptotic stimuli. Expression of calbindin-D(28k) in neural cell suppressed the proapoptotic actions of presenilin-1, which is causally linked to familial Alzheimer's disease, by preventing calcium mediated mitochondrial damage and the subsequent release of cytochrome c. Calbindin, by buffering intracellular calcium can also protect HEK 293 kidney cells from parathyroid hormone induced apoptosis that was found to be mediated by a phospholipase C dependent increase in intracellular calcium. In addition, cytokine mediated destruction of pancreatic beta cells can be prevented by calbindin. Induction by cytokines of nitric oxide, peroxynitrite and lipid hydroperoxide production was significantly decreased in calbindin expressing beta cells. Thus, calbindin-D(28k), by inhibiting free radical formation, can protect islet beta cells from autoimmune destruction in type 1 diabetes. Calbindin-D(28k) can also protect against apoptosis in bone cells. Calbindin was found to block apoptosis in osteocytic and osteoblastic cells. Our findings suggest that calbindin is capable of directly inhibiting the activity of caspase-3, a common downstream effector of multiple apoptotic signaling pathways, and that this inhibition results in an inhibition of tumor necrosis factor (TNFalpha) and glucocorticoid induced apoptosis in bone cells. Thus, while part of calbindin's protective effect may result from buffering rises in intracellular calcium, other mechanisms of action, such as inhibition of caspase activity, also play a significant role in the prevention of apoptosis by calbindin-D(28k). These findings have implications for the prevention of degeneration in different cell types and therefore could prove important for the therapeutic intervention of many diseases, including diabetes and osteoporosis.
J Steroid Biochem Mol Biol 2004 May
PMID:Biological actions and mechanism of action of calbindin in the process of apoptosis. 1522 9

The physiologic range for circulating 25-hydroxyvitamin D3 [25(OH)D; the measure of Vitamin D nutrient status] concentration in humans and other primates extends to beyond 200 nmol/L (>80 ng/mL). This biologic "normal" value is greater than current population norms for 25(OH)D. Concentrations of 25(OH)D that correlate with desirable effects extend to at least 70 nmol/L, with no obvious threshold. Randomized clinical trials using 20 mcg (800 IU) per day of Vitamin D show that this suppresses parathyroid hormone, preserves bone mineral density, prevents fractures, lowers blood pressure and improves balance. Calcium absorption from diet correlates with 25(OH)D in the normal range. Health effects of Vitamin D beyond osteoporosis are mostly supported by the circumstantial evidence of epidemiologic studies and laboratory research. These include prevention of cancer and the autoimmune diseases, insulin-dependent diabetes and multiple sclerosis. One mcg per day of Vitamin D(3) (cholecalciferol) increases circulating 25(OH)D by about 1 nmol/L (0.4 ng/mL). A recommended dietary allowance (RDA) is the long-term daily intake level that meets the total requirements for the nutrient by nearly all healthy individuals (it would presume no sunshine). If 70 nmol/L is regarded as a minimum desirable target 25(OH)D concentration, then current recommendations of 15 mcg per day do not meet the criterion of an RDA.
J Steroid Biochem Mol Biol 2004 May
PMID:Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults. 1522 42

Moderate Vitamin D deficiency causes secondary hyperparathyroidism and bone loss, leading to osteoporosis and fractures. Controversy exists which circulating level of 25-hydroxyvitamin D (25OH)D is appropriate. The high incidence of hip fractures at northern latitudes suggest a relationship with Vitamin D deficiency. However, international studies show lower serum 25(OH)D levels in southern than in northern Europe. Serum 25(OH)D was not a risk factor for hip fractures in several epidemiological studies. The required serum 25(OH)D is usually established by assessing the point where serum parathyroid hormone (PTH) starts to rise. This point varied in several studies between 30 and 78 nmol/l. However, interlaboratory variation may also influence the apparent required serum 25(OH)D level. Dietary calcium intake influences serum PTH and serum PTH may influence the turnover of Vitamin D metabolites. A low calcium intake causes an increase of serum PTH and serum 1,25(OH)2D thereby decreasing the half life of serum 25(OH)D. While a low calcium intake may aggravate Vitamin D deficiency, a high calcium intake may have a Vitamin D sparing effect. With current knowledge, a global estimate for the appropriate serum 25(OH)D is 50 nmol/l.
J Steroid Biochem Mol Biol 2004 May
PMID:Which circulating level of 25-hydroxyvitamin D is appropriate? 1522 48

1,25-(OH)(2) vitamin D(3) is important for calcium homeostasis and cell differentiation. The key enzyme for the activation of liver-derived 25(OH) vitamin D(3) is 25-hydroxyvitamin D(3) 1alpha-hydroxylase. It is expressed mainly in the kidney but also in peripheral tissues. A 1413-bp fragment of the 1alpha-hydroxylase promoter was cloned into luciferase vectors pGL2basic and pGL3basic. Sequence analyses revealed four base exchanges and three base deletions compared with the published sequence which were identically found in five control persons. In silico promoter analyses revealed 17 putative nuclear factor (NF)kappaB sites, 10 of which were found to bind NFkappaB in EMSA experiments. Cotransfection of NFkappaB p50 and p65 subunits resulted in dramatic reduction of the promoter activity of the full-length construct as well as a series of 5'-deletion constructs. Deletion of the farmost 3'-situated NFkappaB-responsive element almost abolished NFkappaB responsiveness. Treatment of human embryonic kidney 293 cells with sulfasalazine, a NFkappaB inhibitor, resulted in enhanced 1alpha-hydroxylase mRNA production. Down-regulation of 1alpha-hydroxylase promoter through NFkappaB signaling may contribute to the pathogenesis of inflammation-associated osteopenia/osteoporosis.
Mol Endocrinol 2004 Oct
PMID:Down-regulation by nuclear factor kappaB of human 25-hydroxyvitamin D3 1alpha-hydroxylase promoter. 1524 30

Osteoporosis or osteopenia occurs in about 44 million Americans, resulting in 1.5 million fragility fractures per year. The consequences of these fractures include pain, disability, depression, loss of independence, and increased mortality. The burden to the healthcare system, in terms of cost and resources, is tremendous, with an estimated direct annual USA healthcare expenditure of about $17 billion. With longer life expectancy and the aging of the baby-boomer generation, the number of men and women with osteoporosis or low bone density is expected to rise to over 61 million by 2020. Osteoporosis is a silent disease that causes no symptoms until a fracture occurs. Any fragility fracture greatly increases the risk of future fractures. Most patients with osteoporosis are not being diagnosed or treated. Even those with previous fractures, who are at extremely high risk of future fractures, are often not being treated. It is preferable to diagnose osteoporosis by bone density testing of high risk individuals before the first fracture occurs. If osteoporosis or low bone density is identified, evaluation for contributing factors should be considered. Patients on long-term glucocorticoid therapy are at especially high risk for developing osteoporosis, and may sustain fractures at a lower bone density than those not taking glucocorticoids. All patients should be counseled on the importance of regular weight-bearing exercise and adequate daily intake of calcium and vitamin D. Exposure to medications that cause drowsiness or hypotension should be minimized. Non-pharmacologic therapy to reduce the non-skeletal risk factors for fracture should be considered. These include fall prevention through balance training and muscle strengthening, removal of fall hazards at home, and wearing hip protectors if the risk of falling remains high. Pharmacologic therapy can stabilize or increase bone density in most patients, and reduce fracture risk by about 50%. By selecting high risk patients for bone density testing it is possible to diagnose this disease before the first fracture occurs, and initiate appropriate treatment to reduce the risk of future fractures.
Clin Mol Allergy 2004 Jul 14
PMID:Management of osteoporosis. 1525 71


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