PubMed Health⌕ Search

Biomedical subjects

D Goltzman

Publications and source records attributed to D Goltzman.

At least 145 records · Page 8Linked to original sources
PubMed1987

Induction of hypocalcemia by intracerebroventricular injection of calcitonin: evidence for control of blood calcium by the nervous system.

Calcitonin (CT), when administered peripherally, is a potent hypocalcemic agent. This peptide can also exert a variety of profound effects through brain receptors after central injection. We examined the capacity of CT to alter plasma calcium of freely moving conscious rats after intracerebroventricular (i.c.v.) injection. A dose-dependent decrease in plasma calcium was seen after administration of 25 ng, 250 ng or 2500 ng of salmon calcitonin (sCT). The extent and duration of hypocalcemia after central injection was equal to, or greater than, that seen after giving the same doses of peptide intravenously (i.v.). Calcitonin gene-related peptide (CGRP), when administered centrally at a 50-fold molar excess, produced only a transient decrease in plasma calcium. No increase in plasma levels of sCT could be detected by RIA after i.c.v. injection, although measurable levels were obtained by i.v. injection. Centrally administered sCT did not appear to produce hypocalcemia by enhancing the release of endogenous rat CT. In contrast to the rise in rat immunoreactive parathyroid hormone (PTH) seen after i.v. injection of sCT, no significant elevation occurred after central administration of the peptide despite induction of comparable levels of hypocalcemia. Consequently, reduced PTH release may contribute to the central hypocalcemic action of CT. The results indicate that peptides acting through the brain CT receptor may modulate peripheral blood calcium.

Animals↗
PubMed1987

Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis.

Hypercalcemia developed in a patient undergoing long-term hemodialysis, and she was found to have noncaseating granulomas on lymph node biopsy. Hydroxychloroquine was administered as therapy for the hypercalcemia. Over 24 weeks of treatment with the drug, concentrations of calcium and 1,25-dihydroxyvitamin D returned to normal. The results demonstrate the capacity of hydroxychloroquine to inhibit the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, and emphasize the efficacy of hydroxychloroquine as an alternate to corticosteroids in the treatment of hypercalcemia of granulomatous disease. Hydroxychloroquine may be preferred when existing skeletal disease, or a predisposition to osteopenia, provides relative contraindications to corticosteroid therapy.

Female↗
PubMed1987

Characteristics of prostate-derived growth factors for cells of the osteoblast phenotype.

We examined the characteristics of mitogens extracted from human benign prostatic hyperplasia and prostatic adenocarcinoma tissue. Although mitogens for fetal rat skin fibroblasts as well as for rat calvarial osteoblasts and osterosarcoma cells were found, distinct entities that acted selectively in cells of the osteoblast phenotype could be obtained by sequential reverse-phase high performance liquid chromatography. Two peptides with apparent molecular weights of 10,000 and 13,000 D were derived from hyperplastic tissue, whereas a single moiety of 10,000 D was obtained from malignant tissue. These entities increased cell numbers and alkaline phosphatase activity in osteoblastlike cells consistent with effects on both growth and differentiation. Prostatic peptides did not stimulate adenylate cyclase in osteosarcoma cells. Mitogenic activity selective for osteoblastlike cells was identified in postpubertal but not prepubertal normal prostate. The results demonstrate the existence of osteoblastic growth factors in prostatic tissue whose presence may accompany postpubertal development.

Adenocarcinoma↗
PubMed1987

Effects of human prostatic mitogens on rat bone cells and fibroblasts.

We examined several characteristics of the mitogenic activity of extracts of human prostatic adenocarcinoma and human benign prostatic hyperplasia in fetal rat calvarial cells, cloned rat osteosarcoma cells and rat skin fibroblasts. Prostatic moieties produced maximal stimulation of [3H]thymidine incorporation at 24 h, were mitogenic in the absence or presence of various concentrations of serum, and were active in calvarial cells enriched with osteoblasts, skin fibroblasts and the cloned rat osteosarcoma cell line UMR 108. The known growth-promoting agents insulin, insulin-like growth factor, fibroblast growth factor, platelet-derived growth factor, epidermal growth factor, interleukin-1 alpha and beta and transforming growth factor beta were also mitogenic in the indicator systems employed; however, maximally stimulating effects of these peptides in cells of the osteoblast phenotype were further enhanced with prostatic material. Prostatic activity was acid-stable and could be enriched with respect to osteoblast stimulation by hydrophobic and carboxymethyl ion-exchange chromatography. The results demonstrate the presence of potent mitogenic activity in hyperplastic and malignant prostatic tissue which appears to include unique osteoblast-stimulating activity.

Adenocarcinoma↗
PubMed1986

Calcitonin receptor binding as a marker of osteoclast heterogeneity in osteopetrotic rodents.

We have employed a radioautographic technique to examine in vivo receptor binding of calcitonin to osteoclasts in four rodent mutants with osteopetrosis. 125I-Labeled calcitonin was injected intravenously alone or with excess unlabeled calcitonin to osteopetrotic (op/op), osteosclerotic (oc/oc), and microphthalmic (mi/mi) mice and to incisor absent (ia/ia) rats. Similar experiments were performed simultaneously in phenotypically normal littermates. Specific binding of calcitonin to receptors on osteoclasts and osteoclast morphology were then examined by light and electron microscope radioautography. Calcitonin binding was increased in mi/mi mice, where osteoclasts were abundant but reduced in size, and was also increased in op/op mice in association with an undulated and redundant osteoclast cell membrane. Binding of the hormone was markedly diminished on osteoclasts of oc/oc mice and ia/ia rats. Thus, in these rodent models of osteopetrosis all of which manifest reduced skeletal remodeling and share a recessive pattern of inheritance, considerable heterogeneity of osteoclast characteristics was demonstrable. Although calcitonin may play no primary pathogenetic role in most forms of this disease, calcitonin receptor binding is a morphological and functional marker of osteoclasts that can be used in assessing the pathophysiology of disorders of bone remodeling.

Animals↗
PubMed1986

Selective osteoblast mitogens can be extracted from prostatic tissue.

Extracts of human prostatic carcinoma and of human benign prostatic hyperplasia were found to exhibit mitogenic activity in freshly isolated rat osteoblasts, rat fibroblasts, and osteoblast-derived osteosarcoma cells. This activity was markedly reduced by tryptic digestion of extracts, indicating its protein nature. Results of bioassay studies suggested that the prostatic material was different from a number of known growth factors. Analysis by reversed-phase high performance liquid chromatography revealed that extracts contained mitogenic activity for osteoblasts that was distinct from fibroblast-stimulating activity. Such osteoblast growth factors could form the basis of the skeletal osteogenic response to metastatic prostatic adenocarcinoma.

Adenocarcinoma↗
PubMed1986

Purification of peptides with parathyroid hormone-like bioactivity from human and rat malignancies associated with hypercalcemia.

We have purified peptides with PTH-like bioactivity from a rat Leydig cell tumor (H-500) and a human squamous cell carcinoma, both associated with a syndrome of humor-induced hypercalcemia. Tumor extracts were shown to be active in an in vitro renal cytochemical bioassay and in an in vitro osteosarcoma cell (UMR 108) adenylate cyclase assay; activity in both assays could be reduced by the PTH antagonist [norleucine-8,18,tyrosine-34]bovine PTH-(3-34)-amide. Partially purified extracts of both tumors and of rat tumor-conditioned culture medium were active in vivo in thyroparathyroidectomized rats in preventing hypocalcemia and increasing fractional phosphorus excretion and cAMP excretion. Ion exchange chromatography demonstrated that active peptides were basic in character. Employing reverse phase HPLC and gel permeation HPLC, active peptides of approximately 9,000 and 9,500 daltons were purified from extracts of the human and rat tumors, respectively, which had similar but not identical compositions. Two additional bioactive peptides were detected in rat tumor extract, and the more active had a mol wt of approximately 28,000. The results demonstrate that peptides that mimic PTH in a variety of in vivo and in vitro bioassays can be extracted from malignancies associated with hypercalcemia, that multiple molecular species may be detected in tumors that demonstrate PTH-like activity, and that at least one of these peptides may be similar in two tumors of highly divergent cell and species origin.

Animals↗
PubMed1986

Parathyroid hormone binding in vivo to renal, hepatic, and skeletal tissues of the rat using a radioautographic approach.

We have examined in vivo binding of bovine (b) PTH-(1-84) and the analog [Nle8,18, Tyr34]bPTH-(1-34) amide to hepatic, skeletal, and renal rat tissues. Bioactive 125I-labeled bPTH-(1-84) or the 125I-labeled bPTH-(1-34) analog was injected alone into experimental animals or with either unlabeled PTH or unlabeled unrelated hormone into control animals. Corresponding tissues from experimental and control animals were then processed for light and electron microscope radioautography and analyzed quantitatively and qualitatively. Binding of both PTH forms occurred on hepatocytes and sinusoidal cells in liver, and hepatocyte binding was clearly specific and competitive. Intact PTH-(1-84), but not the amino-terminal fragment, bound to Kupffer cells, indicating a sequence-specific interaction. In bone, specific competitive PTH binding was seen over osteoblasts, but not osteoclasts. Skeletal PTH binding was also seen over connective tissue mononuclear cells, and sinusoidal endothelial cells. In kidney, specific competitive PTH binding was seen over glomerular podocytes, and over the antiluminal surface of cells of the proximal tubule, the thick ascending limb of Henle's loop, and the distal tubule. Noncompetitive binding was seen on the luminal surface of proximal convoluted tubule cells. We have, therefore, distinguished specific competitive binding sites, probably related to hormone action, from noncompetitive binding sites, presumably associated with hormone metabolism, on discrete cell types or cell regions within several tissues. Our approach provides morphological correlates to the biochemical interaction of PTH with its target tissues and should enhance our understanding of the relationship of target cell structure and function.

Animals↗
PubMed1985

Interaction of calcitonin and calcitonin gene-related peptide at receptor sites in target tissues.

Discrete receptor sites for calcitonin (CT) and calcitonin gene-related peptide (CGRP) were found in the nervous system and in peripheral tissues. Each peptide was capable of cross-reacting with the specific receptor of the other. In contrast to CT receptors, CGRP receptors were not linked to adenylate cyclase. However, CGRP could stimulate adenylate cyclase in CT target tissues apparently by interacting with CT receptors. The relative abilities of CGRP and mammalian CT to inhibit CT binding suggest that CGRP could serve as an endogenous ligand for CT receptors in the central nervous system.

Adenylyl Cyclases↗
PubMed1985

Comparison of renal and osseous binding of parathyroid hormone and hormonal fragments.

We compared receptor binding and adenylate cyclase stimulation of intact bovine parathyroid hormone (bPTH)-(1-84) and the synthetic amino-terminal fragments, bPTH-(1-34) and rat PTH (rPTH)-(1-34). Radioligands for binding studies were prepared by the lactoperoxidase technique and purified by high-pressure liquid chromatography. In both canine renal membranes and cloned rat osteosarcoma cells the amino-terminal fragments bound to a single order of sites; the affinity of rPTH-(1-34) exceeded that of bPTH-(1-34), correlating with its higher potency in stimulating adenylate cyclase. In studies with oxidized bPTH-(1--84), the middle and carboxyl regions of intact PTH were found to bind to both tissues but with higher affinity to osteosarcoma cells than to renal membranes. Our results demonstrate that rPTH-(1--34) is the most favorable probe of amino-terminal PTH binding and the most potent of the PTH peptides in stimulating renal and osseous adenylate cyclase. The results also show that midregion and carboxyl determinants within intact PTH contribute to hormone binding, which does not correlate with adenylate cyclase activation and appears more significant for skeletal than for renal binding.

Adenylyl Cyclases↗
PubMed1985

Calcitonin gene-related peptide mimics calcitonin actions in brain on growth hormone release and feeding.

We have examined the capacity of calcitonin gene-related peptide (CGRP) to exert two biological actions in the central nervous system (CNS): modulation of GH release and alteration of food intake. These effects were compared with those of calcitonin (CT). Intracerebroventricular administration of both rat (r) CGRP (10 micrograms/10 microliter) and salmon (s) CT (250 ng/10 microliter) to chronically cannulated freely-moving rats reduced the frequency and amplitude of spontaneous GH secretory pulses; however, the suppressive effect was of longer duration with sCT than with rCGRP. Both peptides also significantly reduced spontaneous food intake over a 6-h period when administered centrally, although the decrease with sCT was again more extensive than that with rCGRP. The results demonstrate that CGRP can simulate two of the effects of CT in brain. Furthermore, the findings suggest that CGRP may function as an endogenous ligand for CT receptors in the CNS, and participate centrally in the modulation of GH release and the control of satiety.

Animals↗
PubMed1985

Messenger ribonucleic acid from tumors associated with humoral hypercalcemia of malignancy directs the synthesis of a secretory parathyroid hormone-like peptide.

Previous studies have provided evidence that tumors associated with humoral hypercalcemia of malignancy produce a factor that shares certain biological properties with, but is not, native PTH. In the present study, media from Xenopus oocytes microinjected with polyadenylated RNA prepared from three human or animal tumors associated with humoral hypercalcemia of malignancy are shown to have activity in the cytochemical bioassay for PTH. This activity parallels that of the PTH standard in the assay and is completely inhibited by the PTH analog [Nle8,Nle18,Tyr34]bovine PTH-(3-34)NH2. Media from oocytes injected with mRNA from control tumors contain no such activity. The mRNA encoding this activity in one of the animal tumors has been enriched approximately 10-fold by preparative polyacrylamide gel electrophoresis. These results demonstrate that tumors associated with humoral hypercalcemia of malignancy have the capacity for directing the synthesis of a secretory protein that fulfills certain criteria for being the humoral mediator in question. These techniques may provide the basis for molecular cloning of this factor.

Animals↗
PubMed1985

Examination of circulating parathyroid hormone in pseudohypoparathyroidism.

We examined characteristics of circulating PTH in three patients with pseudohypoparathyroidism type I. All patients were normocalcemic while receiving vitamin D therapy at the time of study. In all three, immunoreactive PTH levels were elevated, whereas bioactive levels were low or low normal. Analysis of plasma immunoreactivity by high performance liquid chromatography revealed a relative increase in hydrophobic moieties compared to patterns in patients with other hyperparathyroid states. Plasma or serum from these patients inhibited the stimulatory action of exogenous bovine PTH in an in vitro renal cytochemical bioassay and an in vitro renal adenylate cyclase assay. Such inhibition persisted after partial reduction, in one patient, of circulating immunoreactive PTH levels by an acute calcium challenge. Patient plasma did not bind bioactive 125I-labeled PTH in vitro. The results demonstrate abnormal persistence of elevated immunoreactive PTH levels in normocalcemic patients with pseudohypoparathyroidism, indicate that this circulating hormone may be altered, and suggest that a defect in PTH release and/or metabolism may accompany the other biochemical abnormalities known to occur in this disorder.

Adenylyl Cyclases↗
PubMed1984

Phosphorylation of parathyroid hormone by human and bovine parathyroid glands.

Human and bovine parathyroid gland slices were incubated in vitro for varying time periods with inorganic 32P and [35S]methionine or [3H]serine. Tissue was then extracted with aqueous medium, and parathyroid hormone (PTH) purified. Incorporated 32P was found to coelute with immunoreactive PTH in multiple chromatographic systems, and a peak of phosphorylated material could be resolved from the nonphosphorylated hormone by reversed phase high pressure liquid chromatography. The amino acid composition of both the phosphorylated and the nonphosphorylated entities conformed to that of the major glandular species of PTH, and phosphorylated hormone accounted for 10-20% of the total. A time course revealed slow incorporation of 32P into hormone, and after a 4-h preincubation with inorganic 32P, co-elution of 32P with both PTH and its precursor was observed. Phosphoserine was identified in purified PTH labeled with [3H]serine. Additionally dilute acid hydrolysis of PTH, labeled with [35S]methionine and containing 32P, generated an 35S-labeled fragment with which 32P co-chromatographed. The results are consistent with in vitro phosphorylation of PTH on serine residues within the NH2-terminal region of the hormone by both human and bovine glands and suggest that phosphorylation of the prohormone occurs as well.

Amino Acids↗
PubMed1984

Specific receptors for calcitonin in the subfornical organ of the brain.

A radioautographic method was used to locate specific binding sites for biologically active iodinated calcitonin in rats. The results show that the subfornical organ of the brain, a suspected water regulating organ, is a specific target for calcitonin. The hormone predominantly binds to processes of tanycytes, suggesting that these ependymal cells play an intermediate role between the endocrine and nervous systems.

Animals↗
PubMed1984

Bioactive parathyroid hormone in canine progressive renal insufficiency.

Bioactive parathyroid hormone and hormonal actions were monitored as hyperparathyroidism evolved in a model of progressive canine renal failure. Circulating levels of bioactive and immunoreactive parathyroid hormone rose as renal insufficiency worsened, but elevations, especially in bioactivity, were most marked in the final stage of uremia. By gel filtration analysis, the major circulating bioactive moiety was similar to the major glandular form of parathyroid hormone, although a smaller-molecular-weight entity was seen in the final stage of renal failure. Renal phosphate threshold fell, urinary hydroxyproline corrected for glomerular filtration rose, and plasma 1,25-dihydroxyvitamin D fell but remained detectable, as renal function deteriorated. The results demonstrate a progressive rise in bioactive parathyroid hormone, show the appearance of a small-molecular-weight bioactive entity in severe renal disease, and correlate effects of the rising bioactive parathyroid hormone with changes in renal phosphate handling and with skeletal resorption.

Animals↗
PubMed1984

Discordant disappearance of bioactive and immunoreactive parathyroid hormone after parathyroidectomy.

The disappearance of plasma PTH after parathyroidectomy was assessed in patients with primary hyperparathyroidism and normal renal function, chronic renal failure or restored renal function (after transplantation). Plasma PTH levels were determined by renal cytochemical bioassay and by midregion and carboxyl-terminal RIAs. Baseline PTH levels were lower in each patient when assessed by bioassay than when determined by RIA, and the rate of hormone disappearance was faster when determined by bioassay than when measured by RIA. This difference was accentuated in chronic renal failure due to prolongation of the disappearance rates of midregion and carboxyl-terminal immunoreactivity. The half-life of bioassayable hormone in patients with chronic renal failure was prolonged less than 2-fold compared to the half-life in patients with normal or restored renal function. The results emphasize the discordance between levels of bioactive and immunoreactive hormone regardless of renal function, demonstrate that this discordance is augmented after acute reduction in circulating hormone, and show that it is further increased when kidney function is impaired. The studies also implicate extrarenal mechanisms as a major factor in the clearance of bioactive hormone in established renal failure.

Adult↗