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)

Urinary excretion of hydroxylysyl glycosides, two specific collagen metabolites, was measured in 18 patients with hyperthyroidism and 4 patients with hypothyroidism. As in the case of hydroxyproline, values were high in thyrotoxicosis and low in hypothyroidism. The glucosyl-galactosyl-hydroxylysine/galactosyl-hydroxylysine urinary ratio which indicates the bone or skin origin of degraded collagen was found to be unchanged in hyperthyroidism, except in two cases complicated with hypercalcemia where it was very low. This finding provides a further argument in favour of the bone origin of hypercalcemia in thyrotoxicosis.
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PMID:Urinary excretion of hydroxylysyl glycosides and thyroid function. 111 83

Gallium(III) is a new therapeutic agent for hypercalcemia. Ga3+ reduces osteoclast action, but how it inhibits the cell's physiology is unknown. In vivo, 7-12 microM Ga(III) reduces calcium release from bone, but surprisingly, 10-100 microM Ga3+ added to isolated avian osteoclasts did not reduce their degradation of L-(5-3H)-proline bone. 3H-proline labels bone collagen specifically, and collagenolysis is an excellent indicator of bone dissolution because collagen is the least soluble component of bone. Ga(III) greater than 100 microM inhibited osteoclasts in vitro, but also killed the cells. To resolve this apparent conflict, we measured 67Ga distribution between bone, cells, and media. Gallium binds avidly but slowly to bone fragments. One hundred micrograms of bone clears 60% of 1 microM gallium from 500 microliters of tissue culture medium, with steady state at greater than 24 h. Osteoclasts on bone inhibited gallium binding capacity approximately 40%, indicating a difference in available binding area and suggesting that osteoclasts protect their substrate from Ga binding. Less gallium binds to bone in serum-containing medium than in phosphate-buffered saline; 30% reduction of the affinity constant suggests that the serum containing medium competes with bone binding. Consequently, the effect of [Ga] on bone degradation was studied using accurately controlled amounts of Ga(III) pre-bound to the bone. Under these conditions, gallium sensitivity of osteoclasts is striking. At 2 days, 100 micrograms of bone pre-incubated with 1 ml of 1 microM Ga3+, with 10 pmoles Ga3+/micrograms bone, was degraded at 50% the rate of control bone; over 50 pM Ga3+/micrograms bone, resorption was essentially zero. In contrast, pre-treatment of bone with [Ga3+] as high as 15 microM had no significant effect on bone resorption rate beyond 3 days, indicating that gallium below approximately 150 pg/micrograms bone acts for a limited time and does not permanently damage the cells. We conclude that bone-bound Ga(III) from medium concentrations less than 15 microM inhibits osteoclasts reversibly, while irreversible toxicity occurs at solution [Ga3+] greater than 50 microM.
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PMID:Reversible inhibition of osteoclastic activity by bone-bound gallium (III). 157 77

Parathyroid hormone-related protein (PTHrP) plays a major role in the pathogenesis of malignant hypercalcemia, but has also been found in fetal and adult non-neoplastic tissues. Among them, lactating mammary gland was shown to produce PTHrP, and high levels of PTHrP were measured in milk. However, the regulation of PTHrP production by breast cells is still unknown. Primary cultures of mammary cells isolated from rat lactating glands were grown on collagen gels in an insulin/epidermal growth factor (EGF)-supplemented medium. Under these conditions, mammary cells displayed an epithelial phenotype and their number increased more than twofold after 1 week in culture. At that time, the cells were capable of producing immunoreactive PTHrP (range: 25 to 150 pg/10(5) cells x 24 h) and PTH-like bioactivity, as indicated by a 60% increase in cyclic adenosine monophosphate (cAMP) production induced by mammary epithelial cell conditioned medium in the PTH-responsive osteoblast-like UMR-106 cell line. When cell proliferation was hindered by lowering plating density, by removing medium supplements, or by adding transforming growth factor (TGF)-beta, a well-known autocrine inhibitor of mammary epithelial cell growth. PTHrP production was increased. In contrast, the omission of EGF or addition of specified anti-EGF antibodies decreased PTHrP production. In conclusion, primary cultures of mammary epithelial cells isolated from lactating rat were shown for the first time to produce PTHrP in vitro. This production was higher in the presence of EGF and could be modulated by cell growth rate.
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PMID:Parathyroid hormone-related protein production by primary cultures of mammary epithelial cells. 173 34

Gallium nitrate (GN) is an agent used in the treatment of hypercalcemia. To more fully characterize the direct actions of GN on bone, we examined its effects on medium calcium, medium beta-glucuronidase (beta-GLU), and collagen synthesis in control and hormone-stimulated neonatal (4-6 days) mouse calvariae in vitro. GN (10 micrograms/ml) inhibited parathyroid hormone-stimulated (PTH; 1 nM) calcium release. A 24 h preincubation with 10 micrograms/ml of GN was required for complete inhibition; partial inhibition was seen with 12 h preincubation; 1, 3, or 6 h was inadequate. A dose-response study showed that with 24 h preincubation, 5, 3, and 1 microgram/ml of GN inhibited 81, 62, and 0% of PTH-induced calcium release. The effects of GN on the release of beta-GLU generally paralleled those on the release of calcium except that 10 micrograms/ml of GN stimulated beta-GLU release. Collagen synthesis was inhibited 50% by 3 micrograms/ml of GN, whereas noncollagen protein synthesis was unaffected. With PTH + GN no further decrease was observed. When GN was withdrawn from the medium after 24 h of preincubation, the inhibitory effect on calcium release and beta-GLU activity, but not on collagen synthesis, persisted through the 72 h of culture. GN also inhibited the resorption elicited by thyroxine (1 microM) and interleukin-1 beta (10 nM) but not by 1,25-dihydroxyvitamin D3 (30 pM). Our results indicate that GN is a powerful inhibitor of bone resorption in neonatal mouse calvariae even at low doses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gallium nitrate inhibits bone resorption and collagen synthesis in neonatal mouse calvariae. 179 59

Rapid detection of the exact changes in bone remodelling is exceptionally important. In this paper, the latest bone remodelling biochemical markers are reviewed. Some of them have already been used for a long time, and their utility has been widely demonstrated. The newest ones, in experimental stage, can be used as a complement to the others. The bone remodelling markers reviewed are: 1) Alkaline phosphatase; 2) osteocalcin; 3) Other noncollagen of bone matrix such as osteonectin, GLA-protein of the matrix, osteopontine and alpha 2-HS-glycoprotein; 4) Procollagenous and other collagenous peptides of the matrix (C terminal of type-I procollagen and urinary elimination of nondialysis hydroxyproline. Amongst the bone resorption markers studied are: 1) Calcium/creatinine urinary quotient; 2) Tartrate resistant acid phosphatase; 3) Urinary hydroxyproline; 4) Other substances derived from collagen disruption such as hydroxilysin glycoside, piridinolinic intermolecular bridges and the enzymatic activity of proline iminopeptidase. We endeavoured to collect all the most important references on the matter, especially those relating to Paget's disease of the bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis.
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PMID:[The usefulness of biochemical markers of bone remodelling in the diagnosis and follow-up of Paget's disease of bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis. I. The markers of bone formation]. 210 91

Rapid detection of the exact changes in bone remodelling is exceptionally important. In this paper, the latest bone remodelling biochemical markers are reviewed. Some of them have already been used for a long time, and their utility has been widely demonstrated. The newest ones, in experimental stage, can be used as a complement to the others. The bone remodelling markers reviewed are: 1) Alkaline phosphatase; 2) osteocalcin; 3) other noncollagen of bone matrix such as osteonectin, GLA-protein of the matrix, osteopontine and alpha 2-HS-glycoprotein; 4) Procollagenous and other collagenous peptides of the matrix (C terminal of type I procollagen and urinary elimination of non-dialysis hydroxyproline. Amongst the bone resorption markers studied are: 1) Calcium/creatinine urinary quotient; 2) Tartrate resistant acid phosphatase; 3) Urinary hydroxyproline; 4) Other substance derived from collagen disruption such as hydroxylysine glycoside, piridinolinic intermolecular bridges and the enzymatic activity of proline iminopeptidase. We endeavored to collect all the most important references on the matter, especially those relating to Paget's disease of the bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis.
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PMID:[Usefulness of bone remodelling biochemical markers in the diagnosis and follow-up of Paget's bone disease, primary hyperparathyroidism, tumor hypercalcemia, and postmenopausal osteoporosis. II. Bone resorption markers]. 210 1

Recent reports have fueled an interest in the prevalence and significance of metastatic calcium deposition in patients with chronic hyperparathyroidism. Experimental data are limited by the lack of suitable in vivo animal models. We have developed a model of marked hypercalcemia and overproduction of parathyroid hormone using somatic gene transfer. Briefly, the process involves infection of cultured rodent fibroblasts (RAT-1 cells) with a retroviral expression vector that contains the gene encoding human parathyroid hormone. Fibroblasts are grown to confluence on collagen-coated dextran microcarrier beads and are injected into the peritoneal cavities of syngeneic Fisher rats. Human parathyroid hormone production in rat serum is quantified by an immunoradiometric assay for human parathyroid hormone (1-84), which does not recognize rat parathyroid hormone. These rats consistently show production of human hormone within a week. Levels increase progressively, often to 1 ng/ml within 60 days of injection. Serum calcium showed a concomitant rise to an average of 15.5 mg/dl. In this study, 13 rats that had been transplanted with parathyroid hormone-producing fibroblasts were killed 80 days after injection. Examination of the skeleton revealed demineralization and histopathologic sequelae of parathyroid hormone excess with extensive osteoclastic bone resorption. Examination of the hearts revealed calcification in five of 13 hearts. There was no involvement of major coronary arteries or conducting systems, but there was calcification of cardiac myocytes, primarily in subepicardial region. This model may permit an understanding of the mechanisms for sudden cardiac death in severe hypercalcemia.
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PMID:Evaluation of metastatic cardiac calcification in a model of chronic primary hyperparathyroidism. 224 29

Parathyroid hormone-related peptide (PTHrp), a polypeptide synthesized by tumors associated with hypercalcemia and known to cause bone resorption, was examined for its effects on bone formation in cultures of 21-day fetal rat calvariae. Continuous treatment with PTHrp for 24-72 h stimulated DNA synthesis, but inhibited [3H] proline incorporation into collagen by about 50%. In contrast, transient exposure to PTHrp at 0.1-1.0 nM for 24 h followed by removal of the factor for 48 h caused an increase in [3H]proline incorporation into collagen and noncollagen protein by 2- and 1.6-fold, respectively. The stimulatory effect was seen in the periosteum-free bone, and was decreased, but not prevented by hydroxyurea. PTHrp at 1-10 nM for 24 h increased medium insulin-like growth factor (IGF) I levels by 2.5-4.4-fold, and the effect was sustained 48 h after the removal of the agent. An IGF I neutralizing antibody prevented the stimulatory effect of PTHrp on bone collagen synthesis. PTH had the same stimulatory effects as those of PTHrp on bone collagen synthesis and IGF I concentrations, although slightly lower doses were needed to observe the enhancement of [3H]proline incorporation into collagen. It is concluded that continuous treatment with PTHrp inhibits, whereas transient treatment stimulates, collagen synthesis; the stimulatory effect appears mediated by an enhancement in the local production of IGF I.
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PMID:Differential effects of continuous and transient treatment with parathyroid hormone related peptide (PTHrp) on bone collagen synthesis. 231 43

Proteins with biochemical function and sequence similarity to PTH are produced by many tumors associated with hypercalcemia and may have a role in pathological bone remodeling. Synthetic polypeptides comprising the amino-terminus of human PTH-related protein (PTH-rp) were examined for effects in intact fetal rat calvariae, and in osteoblast-enriched (ob) cultures isolated from fetal rat parietal bone. In cultured calvariae, 0.5-5 nM PTH-rp stimulated [3H]thymidine incorporation into DNA by 25-70% after 24 h of treatment and decreased relative [3H]proline incorporation into collagen by 50%; the inhibitory effect on collagen production was not altered by hydroxyurea, which decreased DNA synthesis by 85%. PTH-rp also increased [3H]hydroxyproline levels by 100% in culture medium from bones prelabeled with [3H]proline, indicating accelerated matrix turnover. In contrast to results in intact calvariae, PTH-rp had little effect on basal DNA and collagen synthesis in serum-deprived ob cultures. However, when ob cultures were treated with transforming growth factor type beta at concentrations similar to those found in calvarial culture medium, 0.02-2 nM PTH-rp enhanced DNA synthesis and decreased collagen production. Furthermore, equimolar PTH-rp and PTH concentrations similarly displaced 125I-PTH-rp binding and enhanced cAMP synthesis in ob cultures. These studies suggest that PTH-rp regulates osteoblastic cell activity primarily through PTH-related pathways and may act in part by modulating the effects of locally produced transforming growth factor-beta in bone.
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PMID:Parathyroid hormone-related protein modulates the effect of transforming growth factor-beta on deoxyribonucleic acid and collagen synthesis in fetal rat bone cells. 273 43

We previously reported that pharmacologic doses of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) given for 2-3 days, inhibited osteoblastic collagen synthesis in young rats. In this study, we tested the effects of 5, 25, and 125 ng of 1,25(OH)2D3 injected subcutaneously into 6-week-old rats for 12 or 18 days. In rats given 125 ng, cortical bone of distal half femurs exhibited decreased calcium (Ca) content but dry weight and hydroxyproline (Hyp) content were no different from control. Trabecular bone Ca was not different from control but dry weight and Hyp were increased. When cortical and trabecular bone were combined, there was a decrease in Ca, an increase in Hyp, and a 50% decrease in Ca:Hyp. Fluorescent labels given after 8 days of treatment were either diffuse or absent in calcified sections from rats given 125 ng, indicating impaired mineralization. The 25 and 125 ng doses produced hypercalcemia with normal serum phosphate. There was a dose-related increase in serum immunoreactive bone gla protein (BGP) and serum 1,25(OH)2D3 and a decrease in serum 25(OH)D3. At the 5 ng dose, no adverse effects were seen on body growth. With 25 ng and 125 ng, growth was inhibited. Increased serum urea nitrogen and histologic evidence of nephrocalcinosis occurred at the 125 ng dose. When 125 ng was given for 12 days and then withdrawn for 6 days, systemic toxicity decreased and bone Hyp and Ca increased so that Ca:Hyp remained low and comparable to that of rats treated with 1,25(OH)2D3 continuously.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of undermineralized matrix formation by 1,25 dihydroxyvitamin D3 in long bones of rats. 308 98


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