Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although calcitonin (CT) treatment has been shown to prevent bone loss in estrogen-deficient states, the function of endogenous CT in bone metabolism is not clearly established. To test the hypothesis that endogenous CT has a role in bone conservation, we compared the bone-resorbing effect of exogenous PTH between CT-deficient [thyroparathyroidectomized (TPTX)] and CT-sufficient [parathyroidectomized (PTX)] rats. Studies were carried out with two doses (30 and 40 pmol/h) of bovine PTH-(1-34) to examine dose responsiveness and with or without T4 replacement in TPTX rats to exclude the influence of thyroid function on the results. Sham-operated control rats received vehicle. At comparable hypercalcemia (mean +/- SEM, 13.6 +/- 0.8 vs. 12.7 +/- 1.0 mg/dl) after 3 days of sc infusion of 30 pmol/h PTH, serum CT levels were significantly (P < 0.05) higher in PTX rats (66.0 +/- 8.0 pg/ml) than in TPTX rats (17.7 +/- 4.3). CT-deficient TPTX rats showed a significant cancellous bone loss in the proximal tibia [bone volume (BV/TV), 4.2 +/- 1.0%] compared with control rats 10.4 +/- 1.2%) In contrast, there was no bone loss in CT-sufficient PTX rats (BV/TV, 10.9 +/- 0.5%). A similar difference in the serum CT level and more marked difference in BV/TV (0.9 +/- 0.3% vs. 8.1 +/- 1.3%) were observed between TPTX and PTX rats infused with 40 pmol/h PTH. The magnitude of bone loss in TPTX rats was not different between T4-supplemented and nonsupplemented groups. Unlike cancellous bone, the PTH-induced decrease in the cortical thickness of the tibia was comparable in TPTX and PTX rats. The extent of increase in serum osteocalcin after PTH infusion was not different between TPTX and PTX groups. These results indicate that in the rat, endogenous CT has a protective effect against PTH-stimulated cancellous bone loss, but not cortical bone loss.
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PMID:Endogenous calcitonin attenuates parathyroid hormone-induced cancellous bone loss in the rat. 783 11

Phosphorus retention as a result of chronic renal failure (CRF) induces secondary hyperparathyroidism (HPT II) while supplemented low-phosphorus low-protein diets (LPD) prevent it. The aim of this study was to assess in seven patients with advanced CRF and biological HPT II the effects of a LPD providing daily 5 to 7 mg/kg phosphorus, 0.4 g/kg protein, 300 mg calcium (Ca) and supplemented with amino acids, ketoacids, CaCO3 and vitamin D2, on the relationship between ionized Ca (iCa) and PTH concentrations. Hyper- and hypocalcemia were induced by CaCl2 and Na2-EDTA infusion. After three months of LPD, serum phosphorus decreased from 1.59 +/- 0.15 to 1.26 +/- 0.24 mmol/liter (mean +/- SEM, P < 0.02), basal PTH levels from 251 +/- 25 to 127 +/- 16 pg/ml (P < 0.03), while basal iCa and GFR did not vary. The sigmoidal PTH-calcium curve shifted downward with maximal PTH decreased from 482 +/- 86 to 319 +/- 60 pg/ml (P < 0.02) and minimal PTH from 35 +/- 4 to 21 +/- 4 pg/ml (P < 0.05). On the other hand, the slope of the % maximal PTH-iCa curve, which is an indicator of the sensitivity of the parathyroid cell to changes in iCa concentrations, did not vary significantly. The set point of Ca and calcitriol levels were not modified. These results demonstrate a direct inhibition of PTH secretion over a wide range of iCa concentration by LPD in patients with advanced CRF and mild HPT II over a three months period. This effect is independent of changes in plasma calcitriol levels.
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PMID:Phosphorus and protein restriction and parathyroid function in chronic renal failure. 785 97

Binding to PTH to its cell surface receptor activates both adenylyl cyclase and phospholipase-C, leading to elevation of cytosolic cAMP and free Ca2+. We have shown previously that extracellular nucleotides interact with P2U and P2Y subtypes of purinoceptor on osteoblastic cells, both linked to Ca2+ mobilization. In the present study, we investigated possible interactions between nucleotide and PTH signaling pathways in osteoblastic cells. The cytosolic free Ca2+ concentration ([Ca2+]i) of UMR-106 osteoblastic cells was monitored by fluorescence spectrophotometry. PTH (0.01-1 microM; bovine 1-84 or human 1-34) induced a small transient elevation of [Ca2+]i, lasting less than 1 min. A number of nucleotides, including ATP, UTP, and UDP, induced transient elevation of [Ca2+]i and potentiated the subsequent Ca2+ response to PTH. Of the nucleotides tested, UDP was the most effective at potentiating the PTH-induced Ca2+ transient. Treatment of cells with UDP (100 microM for 2.5 min), but not inorganic phosphate or uridine, reversibly potentiated the Ca2+ response to PTH (0.1 microM) by 11 +/- 2-fold (mean +/- SEM; n = 39). In contrast, UDP did not affect the cAMP response to PTH, indicating a selective action on Ca2+ signaling. Potentiation of the Ca2+ signal was still observed in the absence of extracellular Ca2+, establishing that nucleotides enhance PTH-induced release of Ca2+ from intracellular stores. Studies using selective purinoceptor agonists suggest that potentiation of PTH signaling is mediated by the P2U receptor subtype. In vivo, nucleotides released during trauma or inflammation may modulate PTH-induced Ca2+ signaling in osteoblasts.
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PMID:Extracellular nucleotides potentiate the cytosolic Ca2+, but not cyclic adenosine 3', 5'-monophosphate response to parathyroid hormone in rat osteoblastic cells. 789 78

Serum PTH concentrations increase with aging and may play an important causal role in age-related bone loss. To better define possible PTH secretory abnormalities with aging, we studied 10 young (aged 27-34 yr) and 10 elderly (aged 71-77 yr) women using sequential infusions of calcium and EDTA. To assess possible age-related resistance of PTH secretion to modulation by 1,25-dihydroxyvitamin D [1,25-(OH)2D], the infusions were repeated after 1 week of oral 1,25-(OH)2D3 therapy (1 microgram/day). Baseline serum intact PTH concentrations were higher in the elderly compared to the young women (mean +/- SEM, 3.8 +/- 0.5 vs. 2.7 +/- 0.4 pmol/L; P = 0.03). In addition, the elderly women had a significantly higher maximal PTH response to hypocalcemia compared to the young women (16.6 +/- 1.1 vs. 12.8 +/- 1.0 pmol/L; P = 0.03). The elderly women also had a greater nonsuppressible component of PTH secretion (0.8 +/- 0.1 vs. 0.4 +/- 0.1 pmol/L; P < 0.001). The set-point for PTH secretion, however, was identical in the elderly and young women (1.18 +/- 0.01 vs. 1.19 +/- 0.01 mmol/L; P = NS). After 1,25-(OH)2D3 administration, both groups had similar reductions in baseline and maximally stimulated PTH levels, indicating that elderly women have normal responsiveness to 1,25-(OH)2D3 suppression of PTH secretion. In addition, maximally stimulated PTH levels in the 1,25-(OH)2D3-treated elderly women decreased to the pretreatment values of young women (13.3 +/- 1.1 vs. 12.8 +/- 1.0 pmol/L; P = NS). thus, elderly women have greater basal, maximal, and nonsuppressible levels of PTH secretion, without alterations in the set-point. These abnormalities are similar to those found in patients with secondary hyperparathyroidism and parathyroid hyperplasia. Further, the abnormal PTH secretory dynamics in elderly women are reversible by short term 1,25-(OH)2D3 therapy.
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PMID:Abnormalities of parathyroid hormone secretion in elderly women that are reversible by short term therapy with 1,25-dihydroxyvitamin D3. 802 29

The widespread expression of the gene for PTH-related protein (PTHrP) and the high interspecies conservation of the primary sequence of even the non-PTH-like portion of the protein argue for a vital role(s) for PTHrP in normal physiology. Emerging evidence suggests that PTHrP may be processed into smaller bioactive peptides, but the circulating forms of PTHrP are not well characterized. We have measured plasma concentrations in well defined patient groups using a RIA directed toward midregion PTHrP-(37-74), compared midregion concentrations to amino-terminal and carboxy-terminal PTHrP concentrations in the same patients, and further defined the components of midregion PTHrP immunoreactivity by high pressure liquid chromatography. Patients with humoral hypercalcemia of malignancy (HHM) had concentrations of PTHrP-(37-74) immunoreactivity of 90 +/- 10 pmol/L (mean +/- SEM), 9-fold higher than PTHrP-(1-74) immunoreactivity and about 3-fold higher than PTHrP-(109-138) immunoactivity. There was no consistent elevation of midregion PTHrP in patients with local osteolytic hypercalcemia, hyperparathyroidism, or renal failure, but discrimination of these groups from HHM was less complete using PTHrP-(37-74) than using PTHrP-(1-74) immunoactivity. By reverse phase high pressure liquid chromatography, plasma PTHrP-(37-74) immunoactivity in patients with HHM was resolved into three components: 1) a major peak coeluting with that found in medium conditioned by cells transfected with human PTHrP-(1-141), which we have previously sequenced and found to represent a midregion peptide beginning at residue 38; 2) a minor peak with both PTHrP-(37-74) and -(1-74) immunoreactivity; and 3) another minor peak with PTHrP-(37-74), but not PTHrP-(1-74), immunoactivity. In conclusion, the predominant circulating form of PTHrP in patients with HHM is a midregion species similar or identical to the peptide beginning at residue 38, which has been shown to be a secretory form of PTHrP.
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PMID:A high abundance midregion species of parathyroid hormone-related protein: immunological and chromatographic characterization in plasma. 810 19

Recent studies have revealed that altered mineral and vitamin D metabolism is observed in diabetic patients with the complication of osteopenia. In order to elucidate the role of parathyroid hormone-related peptide (PTHrP) on calcium homeostasis in diabetes, we have measured the serum level and urinary excretion of PTHrP as well as other serum calcium-regulating hormones in 106 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 43 control subjects. The serum concentration of intact PTH was 2.34 +/- 0.13 (mean +/- SEM) pmol/l in NIDDM patients, which is significantly lower than the value of 3.11 +/- 0.14 pmol/l in the controls (p < 0.01). Both serum calcium and calcitonin, however, were not statistically different from controls. On the other hand, circulating PTHrP in NIDDM was 40.1 +/- 1.4 pmol/l, which is significantly elevated when compared to 27.3 +/- 1.3 pmol/l in the controls (p < 0.01). Moreover, urinary excretion of PTHrP also was significantly higher in NIDDM (p < 0.01). In the present study, the circulating calcium level was well preserved in NIDDM patients, although the PTH levels were shown to be decreased. The elevated serum PTHrP might, therefore, have a physiologically compensatory role on the calcium regulatory systems in NIDDM. Furthermore, this elevation is most likely due to the excess production of this peptide and not to the decrease in urinary excretion.
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PMID:Possible compensatory role of parathyroid hormone-related peptide on maintenance of calcium homeostasis in patients with non-insulin-dependent diabetes mellitus. 810 85

Brush border (BBM) and basolateral membranes (BLM) of rat renal cortical cells separated by free flow electrophoresis revealed two distinct peaks of BBM-specific leucine aminopeptidase and Na+/K(+)-ATPase for BLM. PTH/PTH-related protein (PTHrP) receptors were identified in BBM and BLM. Specific binding of 125 pM [125I]chicken [Tyr36]-PTHrP-(1-36)amide [chPTHrP-(1-36)] to individual fractions of membranes separated by free flow electrophoresis overlapped with the leucine aminopeptidase and Na+/K(+)-ATPase profiles. Binding to pooled BBM was 53 +/- 5% (mean +/- SEM) of that to BLM (P < 0.01). In BBM and BLM, half-maximal inhibition of binding was obtained with 0.4-0.9 nM chPTHrP-(1-36) and 0.2-0.6 nM rat PTH-(1-34). Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S; 100 microM) lowered chPTHrP-(1-36) binding to 50% of control levels, and half-maximal inhibition of binding was obtained with 480 and 8 nM GTP gamma S in BBM and BLM, respectively. Cross-linking of the PTH/PTHrP receptors with [125I]chPTHrP-(1-36) modified with N-hydroxysuccinimidyl-4-azidobenzoate revealed indistinguishable doublets of 83 and 73 kilodaltons in both BBM and BLM. Adenylyl cyclase was stimulated 6- and 10-fold by chPTHrP-(1-36) and GTP gamma S, respectively, in BLM and 1.3- and 1.9-fold in BBM. In conclusion, PTH receptors were recognized in both the basolateral and brush border membranes. Different receptor coupling to G-proteins and minimal cAMP stimulation in BBM provide evidence for PTH/PTHrP receptor isotypes and/or different postreceptor activation in BBM and BLM.
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PMID:Apical and basolateral parathyroid hormone receptors in rat renal cortical membranes. 811 56

Evolution of bone mineral density (BMD) at various skeletal sites and the influence of calcitriol on BMD are still poorly documented in patients with terminal renal failure. Using dual photon absorptiometry, we investigated the changes in BMD at the levels of lumbar spine, femoral neck and midfemoral shaft in 21 patients with end-stage renal failure (ESRF) treated with calcitriol (mean dosage +/- SEM: 0.21 +/- 0.02 microgram/day) and compared them to 25 patients with ESRF but not treated with calcitriol (control group) over a period of 20.3 +/- 1.5 and 17.2 +/- 1.2 months, respectively. Lumbar spine BMD increased by 7.7 +/- 3.2%/year in the treated group and decreased by 2.5 +/- 1.3%/year in the control group (P < 0.005). Femoral shaft BMD increased more in treated than in control group (+ 6.7 +/- 2.3 vs. + 1.4 +/- 2.0%/year; P < 0.05) and femoral neck BMD remained stable. PTH levels increased by 92 +/- 121 and 1033 +/- 254 pmol/year (P < 0.01) in the treated group and the controls, respectively. Osteocalcin changes were -2.7 +/- 3.7 and +20.1 +/- 11.7 micrograms/liter (P < 0.05) per year in the same groups. These results indicate that low doses of oral calcitriol in patients with end-stage renal failure were associated with an increase in BMD at the levels of lumbar spine and femoral shaft, and with a stabilization of serum PTH and osteocalcin concentrations.
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PMID:Effects of oral calcitriol on bone mineral density in patients with end-stage renal failure. 812 15

We report the prolonged biochemical changes that occurred in patients with Paget's disease when treated for 2-10 days with pamidronate disodium (3-amino-1-hydroxypropylidine-1,1-bisphosphonate, APD), by i.v. administration and observed for 6 months following therapy. In all 24 patients studied, bone resorption (measured by urinary hydroxyproline/creatinine ratio, OHP/Cr) fell sharply on treatment, from 0.12 +/- 0.02 (mean +/- SEM; above reference limits) to 0.04 +/- 0.008 (reference range 0.006-0.027 for females, 0.005-0.020 for males), remaining at this level for 6 months after therapy. A fall in serum ionized calcium (Ca2+) to just below the reference limits with treatment (1.11 +/- 0.02 mM; reference range 1.14-1.18 mM), followed by a rapid return to normal levels (1.14 +/- 0.02 mM, mean +/- SEM) within 8 days of treatment, was presumably due to the cessation of release of calcium from bone. This was followed by secondary hyperparathyroidism and a rise in serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. The hormonal responses, however, were profound. Serum immunoreactive PTH (iPTH) rose to twice pretreatment values (86 +/- 11 pM, mean +/- SEM; reference range for iPTH, > 50 years, < 50 pM; < 50 years, < 40 pM), returning to normal 4-8 weeks after therapy. Serum 1,25-(OH)2D levels rose to three times pretreatment values (300 +/- 20 pM, mean +/- SEM; reference range 50-150 pM), remaining above reference limits 4-8 weeks after therapy (188 +/- 15 pM, mean +/- SEM) and returning to normal values only after 12 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Long-term elevation of 1,25-dihydroxyvitamin D after short-term intravenous administration of pamidronate (aminohydroxypropylidene bisphosphonate, APD) in Paget's disease of bone. 815 13

High serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D] can occur with hypercalcemia in malignant lymphoma. We have investigated the potential for abnormal vitamin D metabolism by giving a single oral dose of 25-hydroxyvitamin D (25OHD) in 10 lymphoma patients (8 Hodgkin's and 2 T-cell) and 7 controls. Serum 25OHD increased similarly in both groups (peak concentrations, 114.1 +/- 9.5 vs. 123.9 +/- 9.6 nmol/L). In controls, serum calcium and PTH did not change after treatment [calcium, 2.31 +/- 0.02 and 2.33 +/- 0.02 mmol/L (mean +/- SEM); PTH, 21.6 +/- 4.0 and 25.4 +/- 4.3 ng/L] 1,25-(OH)2D increased within the normal range from [median (range)] 81 (48-125) to 117 (91-156) pmol/L. In lymphoma patients, serum calcium increased from 2.29 +/- 0.04 to 2.40 +/- 0.06 mmol/L (P = 0.03), PTH decreased from 12.9 +/- 2.6 to 8.0 +/- 1.9 ng/L (P = 0.06), and one patient became hypercalcemic (2.92 mmol/L). Serum 1,25-(OH)2D became supranormal in 6 lymphoma patients; the group median rose from 74.5 (46-180) to 151 (120-487) pmol/L; this peak response differed from that in the controls (P = 0.019). Lymph node and spleen cells from a patient with T-cell lymphoma synthesized [3H]1,25-(OH)2D3 from [3H] 25OHD3 in vitro. The data suggest that abnormal production of 1,25-(OH)2D in lymphoma may be more common than previously recognized given an adequate supply of precursor 25OHD and provide further evidence for the extrarenal synthesis of 1,25-(OH)2D in this condition.
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PMID:Abnormal synthesis of 1,25-dihydroxyvitamin D in patients with malignant lymphoma. 817 79


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