Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gallium nitrate, a group IIIa metal salt, has been found to be clinically effective for the treatment of accelerated bone resorption in cancer-related hypercalcemia and Paget's disease. Here we report the effects of gallium nitrate on osteocalcin mRNA and protein levels on the rat osteoblast-like cell line ROS 17/2.8. Gallium nitrate reduced both constitutive and vitamin D3-stimulated osteocalcin protein levels in culture medium by one-half and osteocalcin mRNA levels to one-third to one-tenth of control. Gallium nitrate also inhibited vitamin D3 stimulation of osteocalcin and osteopontin mRNA levels but did not affect constitutive osteopontin mRNA levels. Among several different metals examined, gallium was unique in its ability to reduce osteocalcin mRNA levels without decreasing levels of other mRNAs synthesized by ROS 17/2.8 cells. The effects of gallium nitrate on osteocalcin mRNA and protein synthesis mimic those seen when ROS 17/2.8 cells are exposed to transforming growth factor beta 1 (TGF beta 1); however, TGF-beta 1 was not detected in gallium nitrate-treated ROS 17/2.8 cell media. Use of the RNA polymerase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole demonstrated that gallium nitrate did not alter the stability of osteocalcin mRNA. Transient transfection assays using the rat osteocalcin promoter linked to the bacterial reporter gene chloramphenicol acetyltransferase indicated that gallium nitrate blocked reporter gene expression stimulated by the osteocalcin promoter. This is the first reported effect of gallium nitrate on isolated osteoblast cells.
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PMID:Gallium nitrate regulates rat osteoblast expression of osteocalcin protein and mRNA levels. 838 Dec 50

The objective of the present work has been to study some aspects of bone and intestinal compartments in rats with Walker 256 carcinosarcoma, an experimental model of humoral hypercalcemia of malignancy (HHM). The results have been compared to those obtained in control animals and, also, to those obtained in Yoshida sarcoma-bearing rats, which were used as tumoral controls without hypercalcemia. Urinary hydroxyproline/creatinine ratio (OHProl/creat) is increased, in both Walker 256 and Yoshida tumor-bearing animals, showing the nonspecifity of this bone marker. However, serum tartrate-resistant acid phosphatase (TRAP) levels are increased in Walker 256 tumor-bearing animals, but they are normal in Yoshida tumor-bearing animals, indicating that TRAP is a better index of bone resorption than OHProl/creat in the HHM syndrome. The decrease of bone calcium content in Walker 256 tumor-bearing rats, not shown by Yoshida-bearing rats, also reflects an increased bone resorption due to HHM. Serum and bone osteocalcin levels are similar in control, Walker 256 and Yoshida tumor-bearing rats, but we observed a decrease in serum alkaline phosphatase levels in Walker 256 and Yoshida tumor-bearing animals, which could also be a nonspecific tumor effect, due to the presence of the neoplasia. Our results support the convenience of the employment of a nonhypercalcemic tumor group as control in the HHM study, in addition to the healthy controls. We have also observed higher 1,25-dihydroxyvitamin D serum levels in Walker 256 tumor-bearing rats than in control and Yoshida tumor-bearing rats. On the other hand, we have found normal levels in the fractional rate of intestinal calcium absorption in Walker-256 tumor-bearing rats, in spite of their high calcium levels, and a significant decrease of this parameter in Yoshida sarcoma-bearing animals. These results support the concomitant contribution of intestinal compartment to hypercalcemia, in the experimental model of HHM studied.
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PMID:Osseous and intestinal compartments in the humoral hypercalcemia of malignancy associated to Walker 256 tumor in rats. 845 Oct 38

Burn patients are at risk for bone disease due to aluminum (Al) exposure from use of antacids and albumin, partial immobilization, and increased production of endogenous glucocorticoids. Moreover, severely burned children are growth impaired up to 3 years after the burn. To determine the extent of bone disease, we studied nine men and three women, ages 18-41 years, with greater than 50% body surface area burn. Seven patients underwent iliac crest bone biopsy following double tetracycline labeling, one additional patient expired after a single label, and three others had postmortem specimens obtained for quantitative Al only. Serial serum and urine samples were obtained weekly until biopsy or death. All biopsied patients had reduced bone formation and osteoid area, surface, and width, with mineral apposition rate, osteoblast surface, and osteoclast number with normal eroded surfaces compared to age- and sex-matched normal ambulatory volunteers. Burn patients also had reduced bone formation, mineral apposition rate, osteoid area, and surface compared to age-matched volunteers at short-term bed rest. Serum levels of osteocalcin were low. Most patients had mild hypercalcemia but only a third had hypercalciuria. All patients had elevated Al in blood or urine; urine Al correlated inversely with serum osteocalcin. In 60% significant bone Al was detectable by stain or quantitation. Our data are compatible with burn patients having markedly reduced bone turnover. Al loading, partial immobilization, endogenous corticosteroids, and cytokine production may be among the etiologic factors.
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PMID:Bone disease in burn patients. 845 88

The effects of chronic GH and insulin-like growth factor-I (IGF-I) excess on bone metabolism were examined by measuring serum markers of bone formation and urine markers of bone resorption as well as vertebral bone densities in patients with active acromegaly. Fasting serum GH levels were elevated in all 27 patients (31 +/- 11 micrograms/L). Serum calcium levels were within the normal range, except in 3 of 27 (10%) patients with mild hypercalcemia. Urinary calcium excretion, however, was increased in 6 (22%) patients despite mainly normal serum PTH and 1,25-dihydroxyvitamin D levels, suggesting a direct renal GH and/or IGF-I-mediated calciuric effect. Urinary hydroxyproline/creatinine excretion was increased in all except 1 patient and correlated with plasma IGF-I levels (r = 0.49; P < 0.02; n = 22). A more specific indicator of bone collagen turnover, urinary type I collagen cross-linked N-telopeptide, was elevated in all except 1 patient and correlated with serum GH (r = 0.47; P < 0.02), IGF-I (r = 0.60; P < 0.005), and urinary hydroxyproline/creatinine excretion (r = 0.62; P < 0.001). Serum bone Gla protein (osteocalcin), a specific marker of osteoblastic activity, was also increased in 50% of the patients and correlated with urinary N-telopeptide (r = 0.47; P < 0.02), but not with serum GH or IGF-I concentrations. Trabecular bone density, as determined by quantitative computerized tomography of the lumbar spine, was increased in only 1 patient; 13 others had subnormal bone density. The results suggest that in long-standing acromegaly, osteoblastic and osteoclastic activities are increased. Vertebral trabecular bone mass is usually reduced. Urinary collagen cross-links may serve as a more specific marker of bone resorption in acromegaly.
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PMID:Biochemical assessment of bone formation and resorption in acromegaly. 850 Nov 50

1 alpha,25-Dihydroxycholecalciferol [1,25-(OH)2D3] is a potent differentiating agent in a variety of tumor cell lines. However, the induction of severe hypercalcemia has limited its clinical use. Several analogs have been synthesized that retain the antiproliferative differentiating effects of 1,25-(OH)2D3, but do not have the calcitropic effect of the parent compound. One such analog, 1 alpha,25(OH)2-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), can induce differentiation in HL-60 cells and does not induce hypercalcemia in animal models. We, therefore, evaluated the effect of Ro24-5531 on a human osteosarcoma cell line, MG-63. Compared with 1,25-(OH)2D3, the analog Ro24-5531 is 10-100 times more potent as an inhibitor of MG-63 cell proliferation, as determined by [3H]thymidine incorporation and/or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The inhibition in cell growth is accompanied by a decrease in the expression of p34cdc2 (> 4-fold), a protein critically involved in cell cycle regulation. Ro24-5531 treatment of MG-63, at a concentration of 10(-8) mol/L, induced expression of the bone differentiation markers biglycan and osteocalcin, as determined by Northern analysis. These data suggest that Ro24-5531 treatment induces growth arrest coupled with differentiation. To begin to evaluate the mechanisms by which Ro24-5531 may exert an effect, we evaluated the effect of Ro24-5531 on components of the insulin-like growth factor I (IGF-I) signaling pathway, an important regulator of normal bone growth and differentiation. The expression of IGF-binding protein (IGFBP), IGFBP-3 messenger ribonucleic acid, and protein levels are increased 20-fold after 72 h of treatment with Ro24-5531 and are associated with a marked increase in detectable binding of ligand to binding protein, as measured by RRA. These data suggest an association between Ro24-5531-induced growth arrest and increased expression of IGFBP-3.
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PMID:1 alpha, 25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531) modulation of insulin-like growth factor-binding protein-3 and induction of differentiation and growth arrest in a human osteosarcoma cell line. 855 Aug 1

Intensive training in a humid and warm environment can cause exertional heat stroke (ExHS) and rhabdomolysis (RBD) in military recruits. To investigate the role of vitamin D and monomeric calcitonin (CT) on the calcium metabolism in ExHS with RBD and acute renal failure (ARF), we studied 21 recruits with ExHS (mean age 21.4 years), 7 of which had ARF. Another 11 age-matched recruits with heat exhaustion (HE) and 11 healthy subjects were selected as controls. Our results showed that in 14 ExHS patients without ARF, mean serum creatinine (Cr) levels were significantly higher (151.16 vs. 106.08 mumol/l, p < 0.01), whereas serum osteocalcin (OC) levels were significantly lower (2.22 vs. 4.65 micrograms/l, p < 0.01) than in healthy controls. In 7 patients with ExHS and ARF, the mean serum Cr (774.38 vs. 105.20 mumol/l, p < 0.01), phosphorus (P) (2.26 vs. 1.26 mmol/l, p < 0.05), creatine phosphokinase (CPK) 274,143.97 vs. 85.78 IU/l, p < 0.05), intact parathyroid hormone (I-PTH) (299.81 vs. 18.66 ng/l, p < 0.05) and CT (13.58 vs. 6.63 ng/l, p < 0.01) levels on admission were significantly higher while the mean ionized calcium (iCa) levels were significantly lower than the healthy controls (0.9 vs. 1.18 mmol/l, p < 0.01). The mean serum 25-hydroxyvitamin D [25(OH)D] levels were not significantly different from healthy controls. However, mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels and the ratio of 1,25(OH)2D to 25(OH)D were significantly lower than healthy controls throughout the whole course of ARF. None of the 7 patients with ExHS and ARF developed hypercalcemia during the diuretic phase. Their mean serum I-PTH levels decreased significantly from 299 to 18 ng/l during the recovery phase (p < 0.05). Our study seems to suggest that the abnormal calcium metabolism in this unique patient group is in part caused by persistently decreased renal production of 1,25(OH)2D, although increased monomeric CT levels were associated with hypocalcemia. However, whether or not a causal relationship exists merits further investigation.
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PMID:A prospective study of calcium metabolism in exertional heat stroke with rhabdomyolysis and acute renal failure. 858 23

Bone and vitamin D metabolism are examined in patients with primary hyperparathyroidism (1 degree HPT), humoral hypercalcemia of malignancy (HHM), and local osteolytic hypercalcemia (LOH) with normal renal function. Among the bone resorption markers, T scores of total deoxypyridinoline (Dpyd) were highest in HHM and were significantly higher than those in 1 degree HPT. Among the formation markers, T scores of osteocalcin (OC) were highest in 1 degree HPT but were negative in HHM. The elevation in total Dpyd was associated with an increase in OC in 1 degree HPT, and the ratios of total Dpyd/OC were similar to those in controls. In contrast, many patients with HHM and LOH exhibited elevated total Dpyd and suppressed OC with increased total Dpyd/OC ratios, but the ratios varied widely. Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] was elevated in 1 degrees HPT but was suppressed in HHM and LOH at any serum Ca levels. These results demonstrate that increased bone resorption is associated with enhanced bone formation in 1 degrees HPT but are uncoupled in many of the HHM and LOH patients, and that total Dpyd/OC ratio can be a useful index to estimate the coupling state of bone. It is suggested that the reduction in serum 1,25(OH)2D cannot be explained by an elevation in serum Ca in HHM and LOH, and that the differences in bone and vitamin D metabolism in HHM and LOH from those in 1 degree HPT may be caused by a common mechanism such as the secretion of some cytokines from tumors.
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PMID:Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia. 863 76

The measurement of circulating osteocalcin or bone GLA protein (BGP) constitutes a well established and non-invasive means for evaluating preferentially the bone formation rate, but most available commercial assays suffer from several technical constraints, notably a rapid degradation of BGP at room temperature or after thawing and the inability to measure subnormal values. We evaluated, from a technical and a clinical viewpoint, a newly available two-site sandwich immunoradiometric assay (IRMA) using standard of human origin and two different monoclonal antibodies. The theoretical and functional assay detection limit was 0.3 ng/ml. Concentrations of BGP progressively decreased when the serum was left at 4 degrees C or at room temperature (mean apparent loss of 15% after 24 h). Two cycles of freezing-thawing only lightly reduced the BGP concentrations. The mean (+/- SD) BGP concentration was 19.6 +/- 7.9 ng/ml in healthy subjects (NI, N = 61); the normal range was 8.1-35.6 ng/ml. There was a marked difference between pre- and postmenopausal women: 15.1 +/- 4.4 vs 22.3 +/- 8.4 ng/ml, respectively (p < 0.05). The mean BGP concentration in patients with tumor-induced hypercalcemia (N = 29) was not significantly different from NI, but nine patients (31%) had subnormal levels and five (17%) had elevated BGP levels. Concentrations of BGP were significantly increased in patients with hyperparathyroidism (N = 14) (45.1 +/- 21.0 ng/ml) and significantly lower than NI in patients with hypoparathyroidism (N = 18) (7.3 +/- 4.6 ng/ml). Concentrations of BGP were also measured by a classical radioimmunoassay using bovine standards and tracer; the correlations between both sets of measurements were significant in all groups, except in patients with hypoparathyroidism. In summary, this newly available IRMA for measuring circulating human BGP appears to be quite sensitive, reproducible and robust. It should be especially useful for investigating clinical conditions characterized by a low bone formation rate.
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PMID:Technical and clinical validation of a new immunoradiometric assay for human osteocalcin. 881 Jul 39

We evaluated in normal and hypophosphatemic (Hyp) mice whether changes in serum levels of osteocalcin in response to dietary phosphate supplementation, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) administration were related to perturbations in calcium phosphate homeostasis. In normal mice, serum osteocalcin levels were not altered by phosphate supplementation. In contrast, phosphate supplementation in Hyp mice led to a 2-fold decrease in serum osteocalcin to normal levels after 3 days and to an increase in osteocalcin levels after 14 days. The decrease in osteocalcin was associated with normophosphatemia, severe hypocalcemia, and marked increases in circulating 1,25(OH)2D3 levels, whereas the increase in osteocalcin levels was associated with normophosphatemia and no change in serum calcium and 1,25(OH)2D3. Administration of PTH decreased serum osteocalcin in both genotypes. Infusion of 1,25(OH)2D3 for 3 days elicited increases in serum osteocalcin and calcium levels in normal mice, whereas in Hyp mice it produced significant decreases in osteocalcin levels and no change in serum calcium. However, with a more prolonged infusion of 1,25(OH)2D3, hypercalcemia and increases in serum osteocalcin were induced in mutant mice. Our results suggest that the abnormal osteocalcin response of Hyp mice is not directly attributable to an osteoblast dysfunction but is secondary, at least in part, to perturbations in factors that modulate the osteoblast activity, especially serum calcium and/or PTH.
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PMID:Abnormal modulation of serum osteocalcin by dietary phosphate and 1,25-dihydroxyvitamin D3 in the hypophosphatemic mouse. 886 97

Recently, several reports have suggested that there is a higher incidence of low turnover bone in the absence of aluminium exposure in peritoneal dialysis patients than in hemodialysis patients. Relative hypoparathyroidism with mild hypercalcemia, induced by a positive calcium balance, is considered to be one of the major causes of this disorder. Thus, we recruited 9 continuous ambulatory peritoneal dialysis (CAPD) patients with relative hypoparathyroidism and low bone turnover [intact parathyroid hormone (iPTH) < 50 pg/mL, intact osteocalcin < 10.0 ng/mL] who had been prescribed 1.75 mmol/L calcium (Ca) dialysate for 5.0 +/- 0.3 years. They were then treated by low Ca (1.25 mmol/L) dialysate for nine months without vitamin D and aluminum administration. Intact PTH and bone metabolic markers [intact osteocalcin, alkaline phosphatase (ALP)] were measured every three months. Intact PTH levels increased from 21.1 +/- 3.8 to 159.2 +/- 32.8 pg/mL after the first three months; thereafter, those levels were maintained at around 150 pg/mL. On the other hand, intact osteocalcin levels rose consecutively from 6.7 +/- 1.2 to reach 22.0 +/- 3.8 ng/mL after nine months. Interestingly, the pattern of time course changes between PTH and intact osteocalcin was different. ALP activity did not change during the nine-month period. Corrected serum calcium was significantly decreased (p < 0.001) to approximately 0.25 mmol/L within one month, and the level remained almost the same thereafter. The serum phosphate level did not change without adjusting the original dose of calcium carbonate as a phosphate binder. We concluded that low Ca dialysate (1.25 mmol/L) is effective for the treatment of CAPD-related hypoparathyroidism with low bone turnover.
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PMID:Low calcium (1.25 mmol/L) dialysate can normalize relative hypoparathyroidism in CAPD patients with low bone turnover. 886 14


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