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G D Aurbach

Publications and source records attributed to G D Aurbach.

At least 19 recordsLinked to original sources
PubMed1992

Allelic loss from chromosome 11 in parathyroid tumors.

Parathyroid tumors may occur in a sporadic fashion or, more rarely, as part of a familial syndrome (such as familial multiple endocrine neoplasia type I). The MENI gene has been mapped by linkage analysis to chromosome 11 at band q11-q13, and presumably acts as a tumor suppressor gene. In the present study, which is an extension of our previous studies, we examined 41 parathyroid tumors from patients with familial multiple endocrine neoplasia type I and 61 sporadic parathyroid tumors with markers on chromosome 11, to assess the extent of allelic loss in those tumors. Twenty-four of the MENI-associated tumors (58%) and 16 of the sporadic parathyroid tumors (26%) displayed allelic loss from chromosome 11. The region of overlap of the allelic losses in the MENI-associated tumors enables us to place the MENI gene between PGA centromerically and INT2 telomerically, a region spanning about 7.5 cM. Taken together with locus ordering by linkage analysis, this clearly localizes the MENI gene telomeric to the PGA locus. Our inability to detect allelic loss on chromosome 11 in some parathyroid tumors suggests the existence of other genes involved in the development and/or progression of this subgroup of presumably monoclonal tumors; or that localized events involving the 11q tumor suppressor gene have occurred in some parathyroid tumors whose detection is beyond the sensitivity of our analysis; or that at least some of the specimens analyzed were in fact primarily hyperplastic parathyroid tissue.

Adenoma↗
PubMed1992

Results of a multidisciplinary strategy for management of mediastinal parathyroid adenoma as a cause of persistent primary hyperparathyroidism.

Persistent primary hyperparathyroidism due to mediastinal parathyroid adenoma was effectively treated by either angiographic ablation or median sternotomy in this study of 49 patients managed at the National Institutes of Health since 1977. Each patient presented here with symptomatic persistent primary hyperparathyroidism after failed initial surgical procedures done at other institutions. Each patient underwent extensive parathyroid localization procedures, including selective angiography, and most had a parathyroid adenoma localized to the mediastinum. Angiographic ablation, the deliberate injection of large doses of contrast material into the artery that selectively perfuses the adenoma, was initially successful in 22 of 30 procedures (73%) in 27 patients. Long-term control of persistent primary hyperparathyroidism was achieved in 17 of 27 patients (63%) by angiographic ablation. Each unsuccessful ablation could be easily salvaged by surgical resection. Surgical resection of the parathyroid adenoma by median sternotomy achieved immediate success in 24 of 24 procedures (p2 less than 0.02 versus ablation), and long-term cure in 23 of 23 evaluable patients (p2 less than 0.001 versus ablation). However, ablation did have benefits for the patients in whom it was successfully performed. It was associated with a significantly shorter hospital stay (median, 6 days versus 9 days for sternotomy, p2 less than 0.003), much less pain, and easier recuperation. Complications of each procedure were transient and similar in both groups. Operative resection is the most effective single means to eradicate mediastinal parathyroid adenoma; however, angiographic ablation can provide similar long-term control of hyperparathyroidism in 63% of patients with less pain and shorter convalescence than that seen in patients after median sternotomy. Our results suggest that angiographic ablation should be attempted as the initial procedure for patients with persistent primary hyperparathyroidism caused by an angiographically identified mediastinal parathyroid adenoma. Operation can be reserved for those who fail ablation.

Adenoma↗
PubMed1991

Natriuretic peptide receptors regulate endothelin synthesis and release from parathyroid cells.

Cloned rat parathyroid cells (PTr cell line) that produce parathyroid hormone-related peptide plus endothelin 1 and primary cultures of human parathyroid cells were tested for growth and differentiation responses to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). High- and low-affinity binding sites for ANP were found on PTr cells; BNP appeared to bind to the same receptors with similar affinities. Either ANP or BNP stimulated production of cGMP and caused a 30% decrease in Na(+)-K(+)-Cl- cotransport. Each peptide increased synthesis and secretion of endothelin 1 by PTr cells in a dose-dependent fashion, but cell growth was not affected. Human parathyroid cells (normal and pathological) also responded to ANP or BNP with an increase in cGMP production. The finding of receptors for natriuretic hormones on parathyroid cells with consequent effects on release of endothelin 1 might be of relevance in understanding the clinical association between hyperparathyroidism and hypertension.

Animals↗
PubMed1991

Endothelin as an autocrine factor in the regulation of parathyroid cells.

Endothelin, originally purified from porcine aortic endothelial cells, is widely distributed in tissues and is recognized as a product of epithelial cells, glial cells, and neurons in addition to endothelial cells. We found evidence by mRNA content and immunoreactivity that this peptide is synthesized in rat parathyroid epithelial cells (PT-r cells) and bovine parathyroid chief cells. The peptide synthesized by PT-r cells comigrated with synthetic endothelin 1 in reverse-phase HPLC and was diluted out in radioimmunoassay in parallel with the synthetic peptide. Bovine parathyroid endothelial cells (BPE-1 cells) did not express this peptide. Preproendothelin 1 mRNA expression by PT-r cells and endothelin 1 peptide production were regulated by calcium. Shifts in extracellular calcium either from high to low concentrations or vice versa elicited similar evanescent increases in expression of mRNA with a peak at 1 h. Synthesis of the peptide seems to be controlled by mRNA expression, and peptide in the medium appears to be continuously degraded or taken up by cells because its concentration in the medium showed a time course similar to that of mRNA expression. PT-r cells also bear a single class of receptors highly specific for endothelin 1, suggesting an autocrine regulation by endothelin 1 of the parathyroid. The facile regulation of endothelin concentrations in the medium by shifts in extracellular calcium concentration and possible autocrine regulation by endothelin 1 suggest that this peptide may mediate, at least in part, effects of calcium on the parathyroid system.

Animals↗
PubMed1991

Identification of heparan sulfate proteoglycan as a high affinity receptor for acidic fibroblast growth factor (aFGF) in a parathyroid cell line.

We have characterized two high affinity acidic fibroblast growth factor (aFGF) receptors in a rat parathyroid cell line (PT-r). Affinity labeling with 125I-aFGF showed that these two receptors, apparent molecular masses, 150 and 130 kDa, respectively, display higher affinity for aFGF than for bFGF. The 150-kDa receptor bears a heparan sulfate chain(s), demonstrated by a decrease in size of 15-20 kDa with heparitinase digestion after affinity labeling. Heparitinase digestion before affinity labeling markedly reduced the intensity of the 150 kDa species. Scatchard analysis showed two different high affinity binding sites (Kd of 3.9 pM with 180 sites/cell and Kd of 110 pM with 5800 sites/cell). The higher affinity site was completely eliminated by digestion with heparitinase before adding labeled aFGF; the lower affinity site was unaffected. In ion exchange chromatography after metabolic labeling of the cells with [3H]glucosamine and affinity labeling with 125I-aFGF, the larger receptor-ligand complex, 165 kDa, eluted with approximately 0.5 M NaCl, typical eluting conditions for heparan sulfate proteoglycans. Both of the receptor-ligand complexes were smaller on sodium dodecyl sulfate-polyacrylamide gel electrophoresis than two major heparan sulfate proteoglycans, HSPG I and II, which we characterized in this cell line previously (Yanagishita, M., Brandi, M. L., and Sakaguchi, K. (1989) J. Biol. Chem. 264, 15714-15720). Both receptors have similar N-linked oligosaccharide and sialic acid contents, shown by analysis of affinity-labeled receptors upon digestion with glycopeptidase F and with neuraminidase. All together, these results suggest that PT-r cells bear two distinct high affinity receptors for aFGF, a 150-kDa receptor which is a heparan sulfate proteoglycan and another that is a glycoprotein. The heparan sulfate glycosaminoglycan moiety of the 150- kDa receptor is critical for high affinity binding of aFGF. These findings contrast with current concepts derived from other systems, suggesting that heparan sulfate glycosaminoglycans/proteoglycans function as a reservoir source for FGF or as a group of low affinity binding sites.

Animals↗
PubMed1991

Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1.

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, pancreatic islets, and anterior pituitary. The gene for this disease maps to chromosome 11q12-11q13, and allelic loss in this region has been shown in both sporadic and FMEN1-related parathyroid tumors. FMEN1-related pancreatic islet tumors, and rarely in sporadic anterior pituitary tumors. We tested for allelic loss at 7 loci on chromosome 11 in 17 tumors outside the parathyroid. We found loss of heterozygosity in 2 of 2 FMEN1-related benign pancreatic islet tumors but in none of 8 informative sporadic islet tumors (P = 0.02) including 5 malignant gastrinomas. Of 3 islet tumors from patients who had some but not all features of FMEN1, one showed allelic loss for 5 of 5 informative restriction fragment length polymorphisms, and the other 2 retained heterozygosity for all informative markers. A bronchial carcinoid from an FMEN1 patient and 3 sporadic anterior pituitary tumors showed no allelic loss. These data provide new evidence that many sporadic pancreatic islet neoplasms, even when malignant, do not develop through homozygous inactivation of the MEN1 gene.

Adenoma, Islet Cell↗
PubMed1991

Locally recurrent parathyroid neoplasms as a cause for recurrent and persistent primary hyperparathyroidism.

Between 1982 and 1989, 145 patients underwent operations for persistent or recurrent primary hyperparathyroidism (HPT). At re-exploration, 15 patients (10.3%) were found to have locally recurrent parathyroid tumors (11 patients with adenoma and 4 with carcinoma). These 15 patients had 28 previous operations at outside institutions for HPT. Patients with locally recurrent HPT secondary to adenoma had a longer disease-free interval than patients with locally recurrent carcinoma. At the time of evaluation at the National Institutes of Health (NIH) for recurrent or persistent HPT, each patient was symptomatic and patients with carcinoma had significantly more symptoms and higher serum levels of calcium and parathyroid hormone than patients with adenoma. Locally recurrent parathyroid neoplasm was correctly localized by preoperative testing in 14 of 15 patients. These 15 patients underwent 18 reoperations at NIH for excision of locally recurrent parathyroid tumors. Following the final reoperation (two patients had more than one procedure), each patient had normal serum levels of calcium. In addition each patient remains biochemically cured (based on normal serum calcium level), with a median follow-up interval of 21 months. Local recurrence of parathyroid adenoma comprises a small but significant proportion of cases of recurrent or persistent HPT and can be indistinguishable from parathyroid carcinoma. Findings suggestive of carcinoma include shorter disease-free interval, higher serum levels of calcium and parathyroid hormone, and histologic appearance. Whether the locally recurrent parathyroid neoplasm is benign or malignant, aggressive surgery can control serum levels of calcium in these patients with acceptable rates of morbidity.

Adenoma↗
PubMed1991

Heterogeneous size of the parathyroid glands in familial multiple endocrine neoplasia type 1.

OBJECTIVE: We wished to determine whether there was size heterogeneity of the parathyroid glands in patients with familial multiple endocrine neoplasia type 1 (FMEN1) and primary hyperparathyroidism. DESIGN: At the National Institutes of Health we performed a retrospective analysis of parathyroid gland volume either from initial or repeat parathyroid exploration. PATIENTS: We studied subjects with FMEN1 and primary hyperparathyroidism. MEASUREMENTS: The parathyroid gland volume was estimated from recorded orthogonal diameters. Volume could also be estimated conservatively in many glands for which one or more diameters were not recorded. Reproducibility of volume measurements was tested with a series of clay gland models. Indices of variability (among glands at an operation or among replicate measurements of a clay model) were the ratio of maximum volume/minimum volume and the average standard deviation of the log volume. RESULTS: The most complete data were from eight initial operations with three dimensions recorded for all four glands. Volume heterogeneity was indicated by the average ratio of 9.6 for the maximum/minimum gland volume within an operation. The size heterogeneity was even greater among other subgroups. For example, the average ratio of maximum/minimum gland volume within an operation was 17 among five initial operations with four glands removed, but lacking measurements of three dimensions for some glands. Little of this size heterogeneity could be attributed to measurement error since eight replicate measurements on a model gland yielded a maximum/minimum volume ratio of 1.45. CONCLUSIONS: There is a wide heterogeneity in size of the parathyroid glands in the patients with FMEN1 and primary hyperparathyroidism.

Humans↗
PubMed1990

Extracellular calcium regulates distribution and transport of heparan sulfate proteoglycans in a rat parathyroid cell line.

The regulation of the cellular distribution of proteoglycans in a clonal rat parathyroid cell line by extracellular Ca2+ concentrations ([Ca2+]e) was studied. Proteoglycans synthesized by the cells metabolically labeled with [35S]sulfate have been shown to be almost exclusively heparan sulfate (HS) proteoglycans (Yanagishita, M., Brandi, M.L., and Sakaguchi, K. (1989) J. Biol. Chem. 264, 15714-15720), which are generally associated with the plasma membrane. The proportion of HS proteoglycans on the cell surface was approximately 20% in 2.1 mM (high) [Ca2+]e, whereas it increased to 50-60% in 0.05 mM (low) [Ca2+]e. Cell-associated HS proteoglycans redistribute in response to changing [Ca2+]e with a t 1/2 less than 4 min; HS proteoglycans appear on the cell surface as [Ca2+]e decreases and disappear from the cell surface as [Ca2+]e increases. Further, HS proteoglycans on the cell surface recycle to and from an intracellular compartment approximately 10 times before their degradation in low [Ca2+]e but do not recycle in high [Ca2+]e. The distribution of newly synthesized HS proteoglycans is regulated by [Ca2+]e but is independent of [Ca2+]e during biosynthesis. In low [Ca2+]e, at least 50% of the HS proteoglycans pulse-labeled for 10 min are transported from the Golgi complex to the cell surface or to the recycling compartment with a t 1/2 of approximately 20 min. Another approximately 10% appear on the cell surface in either low or high [Ca2+]e in a compartment with a long half-life. Addition of Mg2+ or Ba2+ to the low [Ca2+]e cultures had little effect on the distribution of HS proteoglycans. These observations suggest that [Ca2+]e specifically regulates the distribution and recycling of cell-associated HS proteoglycans in the parathyroid cells.

Animals↗
PubMed1990

Subclones of a rat parathyroid cell line (PT-r): regulation of growth and production of parathyroid hormone-related peptide (PTHRP).

Four subclones from a rat parathyroid cell line (PT-r cell) have been isolated, and morphological and functional characteristics have been examined. Subclones 1 and 2 display a polygonal shape, show growth and secretory responses to calcium (half-maximal suppressions at 1.2 and 1.7 mM, respectively), and respond to secretin with cAMP production (14.5-fold and 16.9-fold over basal) and hormone secretion (41 and 58% over basal). Subclone 4 is elongated in form and does not respond to calcium or secretin. Subclone 3 shows mixed morphology, elongated and polygonal shapes, with moderate response to calcium (half-maximal suppression at 1.7 mM) and secretin (cAMP, 3.2-fold increase and hormone secretion, 50% increase over basal). The clones were tested for content of messenger RNA (mRNA) representing parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHRP). Only PTHRP mRNA was found. The peptide released is virtually all PTHRP. PTH mRNA was not detected even with a sensitive RNA probe. The amount of mRNA for PTHRP closely paralleled the amount of PTH-like bioactivity released into the medium from each clone (144.7 +/- 12.1, 110.0 +/- 12.9, 68.0 +/- 5.6, and 39.9 +/- 2.4 pgEq of rat PTH-(-34) per 10(7) cells per 12 h in a medium with 0.7 mM ionized calcium, from subclones 1, 2, 3, and 4, respectively). Culture conditions, low-density passage (less than 1:50 split ratio) or high-density passage (greater than 1:10 split ratio), affected morphology and function of the clones 1 and 2. They became elongated and functionally dedifferentiated like subclone 4 and 3 months of high-density culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Establishment and characterization of a clonal line of parathyroid endothelial cells.

We have isolated endothelial cells derived from bovine parathyroid tissue. These cells have been cloned and maintained by serial passage for more than 40 months without showing signs of senescence. Prolonged culture was accomplished by using a medium favoring endothelial cell growth and methods for enriching endothelial cells in primary culture. The cloned parathyroid endothelial cells contained factor VIII-related antigen, took up acetylated low-density lipoproteins and parathyroid hormone, and showed morphological features comparable to other endothelial cells. Bovine parathyroid endothelial cells replicated with a mean doubling time of 65 h. Fibroblast growth factors, platelet-derived growth factor, and calcium acted as mitogens for parathyroid endothelial cells, whereas transforming growth factor beta inhibited proliferation.

Animals↗
PubMed1990

Circulating fibroblast growth factor-like substance in familial multiple endocrine neoplasia type 1.

Basic fibroblast growth factor (bFGF) is a potent endothelial cell mitogen found in a variety of normal and tumor tissues. Basic FGF lacks a classical signal sequence, and it is not clear how it is released from cells. bFGF or bFGF-like activity has not been previously demonstrated in plasma. In an earlier study we showed increased mitogenic activity for parathyroid-derived epithelial and mesenchymal cells in plasma of subjects with familial multiple endocrine neoplasia type 1 (FMEN1). In the present study we examined the growth-promoting activity of normal and FMEN1 plasmas [applied to heparin-Sepharose (HS) columns] in parathyroid-derived cloned endothelial cells. FMEN1 plasma HS-adsorbed activity exceeded normal plasma HS-adsorbed activity in 6 of 8 FMEN1 plasma samples. Peak (FMEN1 plasma) HS-adsorbed activity eluted with 0.1-0.3 M NaCl, was completely neutralized by specific antibodies against bFGF, and had an apparent mol wt of 110 kD. Active fractions from FMEN1 plasma prepared by gel filtration in 7 M urea displayed apparent mol wt of about 14-16 kD and showed increased apparent affinity for HS; recovered activity appeared principally in the 3.0-M NaCl eluate. Using a sensitive two-site immunoradiometric assay for bFGF we found 0.4 ng/mL bFGF-like immunoreactivity in the highly purified 3.0-M NaCl eluate from a HS column to which the active components from gel filtration of FMEN1 plasma in 7 M urea were applied. These results imply that bFGF or closely related factors circulate in FMEN1.

Adult↗
PubMed1990

Genetic abnormalities in sporadic parathyroid adenomas.

We analyzed genomic DNA from 43 sporadic benign parathyroid adenomas for rearrangements of the PTH gene, and for point mutations of the H-ras (codons 12, 13, and 61), N-ras (codons 12, 13, and 61), and K-ras (codons 12 and 13) genes. One of 43 parathyroid adenomas showed a chromosome 11 rearrangement involving both the PTH gene on the short arm of chromosome 11 (at band p15) and a locus on the long arm (11q13). This rearrangement was indistinguishable from one that was previously described in a parathyroid adenoma by Arnold et al., indicating that this may be an important contributor to tumorigenesis in a small subset of patients with parathyroid adenoma. H-ras, K-ras, and N-ras oncogene activation by point mutation at codons 12, 13, or 61, known to occur in many tumors, could not be detected in any parathyroid adenoma.

Adenoma↗
PubMed1989

Clonal rat parathyroid cell line expresses a parathyroid hormone-related peptide but not parathyroid hormone itself.

A novel parathyroid hormone-related peptide has been identified in tumors associated with the syndrome of humoral hypercalcemia of malignancy. Subsequently, mRNAs encoding this peptide have been found to be expressed in a number of normal tissues, including the parathyroids. Using Northern blotting, RNase protection, and immunochemical techniques, we examined a clonal rat parathyroid cell line originally developed as a model system for studying parathyroid cell physiology. We found that this line expresses the parathyroid hormone-related peptide but not parathyroid hormone itself. Secretion of the parathyroid hormone-related peptide varied inversely with extracellular calcium concentration, but neither calcium nor 1,25-dihydroxyvitamin D3 appeared to influence steady-state parathyroid hormone-related peptide mRNA levels. This clonal line may prove to be an interesting system for studying the factors responsible for tissue-specific parathyroid hormone and parathyroid hormone-related peptide gene expression.

Animals↗
PubMed1989

Cloned endothelial cells from fetal bovine bone.

Primary cell cultures from fetal bovine sternum were developed in Coon's modified Ham's F-12 medium containing 10% Nu-Serum, 1% Ultroser-G, and 200 mg of galactose per liter. Clones were obtained by colony isolation; one clone, BBE-1, was selected for characterization. BBE-1 cells exhibited typical endothelial morphology by light and electron microscopy and immunofluorescence for factor VIII-related antigen throughout their life span of 8 months. The cells showed mitogenic responses to endothelial cell growth factor, basic fibroblast growth factor, insulin-like growth factor types I and II, platelet-derived growth factor, ascorbic acid, and progesterone. Parathyroid hormone stimulated intracellular accumulation of cAMP in BBE-1 cells but not in endothelial cells from two other tissues. These clonal cells provide a useful system for studies on bone vasculature, including its interactions with other bone cells.

Animals↗
PubMed1989

Inhibition of parathyroid hormone release by maitotoxin, a calcium channel activator.

Maitotoxin, a toxin derived from a marine dinoflagellate, is a potent activator of voltage-sensitive calcium channels. To further test the hypothesis that inhibition of PTH secretion by calcium is mediated via a calcium channel we studied the effect of maitotoxin on dispersed bovine parathyroid cells. Maitotoxin inhibited PTH release in a dose-dependent fashion, and inhibition was maximal at 1 ng/ml. Chelation of extracellular calcium by EGTA blocked the inhibition of PTH by maitotoxin. Maitotoxin enhanced the effects of the dihydropyridine calcium channel agonist (+)202-791 and increased the rate of radiocalcium uptake in parathyroid cells. Pertussis toxin, which ADP-ribosylates and inactivates a guanine nucleotide regulatory protein that interacts with calcium channels in the parathyroid cell, did not affect the inhibition of PTH secretion by maitotoxin. Maitotoxin, by its action on calcium channels allows entry of extracellular calcium and inhibits PTH release. Our results suggest that calcium channels are involved in the release of PTH. Inhibition of PTH release by maitotoxin is not sensitive to pertussis toxin, suggesting that maitotoxin may act distal to the site interacting with a guanine nucleotide regulatory protein, or maitotoxin could interact with other ions or second messengers to inhibit PTH release.

Animals↗