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ABSTRACT
Calcitonin (CT) is produced ectopically from a variety of non-thyroidal cancers. The CT genes also encode another peptide, calcitonin gene-related peptide (CGRP) which is a potent vasodilator. In the present study we have used immunochemical and chromatographic methods to demonstrate the presence and characterize the molecular forms of CGRP in cultured human cancer cells. Using two highly sensitive and specific radioimmunoassays, we have detected immunoreactive CGRP (i-CGRP) in cell extracts and cell-exposed media of cultured promyelocytic leukaemia (HL60) and bronchogenic carcinoma (BEN) cells. The mean i-CGRP content of the HL60 and BEN cell extracts was 2 and 45 pmol/g wet weight respectively. On gel filtration and high performance liquid chromatography, the immunoreactive material was found to be heterogeneous, though a major proportion co-eluted with synthetic human CGRP(1–37), suggesting structural identity with the intact CGRP molecule. Finally, we have discussed some interesting features of CT-gene peptide expression in tumour cells.
Journal of Endocrinology (1989) 123, 159–165
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ABSTRACT
Calcitonin inhibits osteoclastic bone resorption and its action involves two separate acute effects on the osteoclast, both essential to the action of the hormone: abolition of cell motility (Q) and marked cellular retraction (R). The former was mimicked by dibutyryl cyclic AMP and cholera toxin and the latter by pertussis toxin, ionomycin and increases in ambient calcium. Aluminium fluoride ions produced both Q and R effects, while lithium prevented both. In addition, calcitonin elicited a biphasic elevation of cytosolic-free calcium in single isolated osteoclasts. We propose that the action of calcitonin is mediated by at least two G proteins, one responsible for the Q effect and the other for the R effect. In addition, two second messengers, cyclic AMP and calcium, are involved. These findings may help to explain the potency of calcitonin in inhibiting bone resorption, and may allow the rational design of new therapeutic agents designed to alter osteoclast behaviour.
Journal of Endocrinology (1990) 126, 473–481
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ABSTRACT
The propensity of ionic lithium to interfere with the coupling of receptors to guanine nucleotide binding proteins (G-proteins) has only recently been investigated using rat cortical membranes. In the present study we have used intact isolated osteoclasts to investigate lithium-induced uncoupling of the receptor-mediated actions of calcitonin. All actions of calcitonin on the osteoclast were abolished by ionic lithium. We believe that the cation prevents signal transduction by inhibiting G protein-receptor interaction, the first step in intracellular signalling.
Search for other papers by J. P. WHALEN in
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Search for other papers by I. MACINTYRE in
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SUMMARY
After calcitonin injection, parathyroidectomy, or both, in young growing rats, broadening of the proximal femoral metaphysis with lack of normal concavity of the medial and lateral contours was observed radiographically. Histologically, this abnormal modelling was associated with retarded osteocytic osteolysis. Further manifestations of decelerated resorption included retention and extension of the chondroid core in the secondary spongiosa, retention of cartilage in the cortex and a large increase in the number of cementing lines.
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To investigate whether human calcitonin (hCT) is preserved during the evolution of vertebrates, we studied extracts of avian (pigeon and chicken) thyroid and ultimobranchial glands (UBG) which have previously been reported to contain salmon calcitonin (sCT) -like molecules. A sensitive and specific radioimmunoassay for hCT, employing two antisera reacting with different regions of the molecule, was used in combination with high performance liquid chromatography (HPLC). We found that extracts of thyroid and UBG from pigeons and chickens contain, in addition to an immunoreactive sCT-like molecule (which is the major immunoreactive form), an hCT-like molecule comprising from 0·4 to 3·75% of the calcitonin content. The extracts produced full displacement of 125I-labelled hCT from both antisera and gave a parallel displacement curve. With HPLC, we found an immunoreactive hCT peak which was 5 ml earlier than the insulin marker and an immunoreactive sCT peak which was 12 ml later than the insulin marker. These results demonstrate the presence of two calcitonins in birds, and suggest the existence of two genes with different degrees of expression.
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ABSTRACT
The calcitonin gene encodes a small family of peptides: calcitonin, calcitonin gene-related peptide (CGRP) and katacalcin. Whereas calcitonin is concerned with skeletal maintenance, the function, if any, of katacalcin is still unknown. In the present study we have assessed resorption of human cortical bone substrate by isolated rat osteoclasts and have shown that CGRP acts directly on the osteoclast to inhibit bone resorption. The three CGRP peptides (rat, human(a) and human(β)) caused an almost equivalent decrease in osteoclastic bone resorption and were approximately 1000-fold less potent than human calcitonin in this respect. The responses of human calcitonin and human CGRP(α) were additive. Furthermore, prior treatment with trypsin to destroy receptors abolished the responsiveness of osteoclasts to CGRP and calcitonin. The carboxyl- and amino-terminal fragments of CGRP were found not to inhibit bone resorption, suggesting that the whole molecule of CGRP is necessary for biological activity. We have therefore suggested that the calcitonin-like effects of CGRP, seen both in vivo in the rat bioassay and in vitro in organ cultures, are due to the direct action of CGRP on the osteoclast, probably mediated through the calcitonin receptor. Though it is unlikely that CGRP is involved in the regulation of plasma calcium, the peptide may be an important local regulator of bone cell function.
J. Endocr. (1987) 115,511–518
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Search for other papers by I. MacINTYRE in
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SUMMARY
The effect of nephrectomy on the response to thyrocalcitonin was studied in three groups of rats: intact animals on stock diet; parathyroidectomized rats on stock diet; and parathyroidectomized rats on high calcium, low phosphorus diet.
In intact rats and in parathyroidectomized rats on a high calcium, low phosphorus diet, nephrectomy did not alter the fall in plasma calcium and phosphate produced by thyrocalcitonin. In parathyroidectomized rats on stock diet, however, plasma calcium was not changed by the hormone, but there was an isolated fall in phosphate which was prevented by previous nephrectomy.
Experiments with 45Ca showed that when plasma calcium was lowered by thyrocalcitonin this was caused by inhibition of bone resorption.
Since the hormone also causes phosphaturia, it was concluded that there are two sites of action: bone and kidney. The skeletal effect is usually dominant and the renal effect is the major one only when the rate of bone resorption is low.
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ABSTRACT
It is known that in addition to the calcitonin precursor the calcitonin gene also encodes a novel peptide, calcitonin gene-related peptide (CGRP). This potent vasodilator has been found in the circulation of man. This present study demonstrates that CGRP is also found in the circulation of the rat and that plasma CGRP comes from two different sources: the thyroid, a major source in old rats, and the perivascular nerves probably at all ages.
J. Endocr. (1986) 110, 185–190
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A molecule very closely resembling human calcitonin immunologically and chromatographically was extracted from the nervous systems of several protochordates and a cyclostome, Myxine. The presence of human calcitonin-like molecules in the nervous systems of primitive chordates suggests that they have some function in the nervous system of these species and that the bone-regulating function of the calcitonins may have arisen much later in the vertebrates.
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ABSTRACT
Amylin-amide has been implicated in the pathogenesis of type II diabetes due to its proposed inhibitory effect on insulin release from β cells of the pancreatic islets, and on glucose uptake by the skeletal muscle. In experiments with rats and rabbits we failed to demonstrate these anti-insulin actions of amylin and amylin-amide. A single bolus dose of the two peptides (500 pmol) administered i.v. failed to supress plasma insulin levels or to elevate blood glucose levels. The continuous infusion of amylin-amide into rabbits also failed to supress the release of insulin in response to hyperglycaemia produced by an i.v. bolus injection of glucose. These in vivo observations imply that the amylin peptides may not have a primary physiological role in carbohydrate metabolism, but in view of our previous findings, we speculate that the peptide has a more prominent role in calcium homeostasis.
