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S. M. A. ZAIDI
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H. HELLER
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Three groups of workers (Heller, Hasan & Saifi, 1968; Vorherr, Bradbury, Hoghoughi & Kleeman, 1968; Unger & Schwarzberg, 1970) have found that stimuli which are known to release endogenous vasopressin (vagal stimulation, haemorrhage, barbiturate anaesthesia) raised the antidiuretic activity (ADA) in the cerebrospinal fluid (CSF) of experimental animals (rabbits, dogs). The nature of the stimuli, the fact that the ADA was abolished by thioglycollate and the recent finding of neurophysin in the CSF (Robinson & Zimmerman, 1973) indicate strongly that the ADA was exerted by vasopressin. However, it is not clear whether the hormone is directly secreted into the CSF by juxtaependymal processes of neurosecretory neurones as suggested by morphological evidence (for references see Heller et al. 1968; Heller & Zaidi, 1974) or whether it reaches the CSF from the blood.

Heller et al. (1968) and Vorherr et al. (1968) have tried to solve this problem by administering vasopressin intravenously

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M. Zaidi
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L. H. Breimer
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I. MacIntyre
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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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M. Zaidi
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H. K. Datta
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B. S. Moonga
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I. MacIntyre
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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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M. Zaidi
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A. Patchell
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H.K. Datta
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I. MacIntyre
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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.

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A. A. Zaidi
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M. H. Qazi
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E. Diczfalusy
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Five highly purified human pituitary LH preparations (candidate preparations for a new International Reference Preparation (IRP) and coded A to E) and three highly purified commercial preparations (referred to as Kabi I, II and III) were fractionated by electrofocusing on a sucrose density gradient with ampholytes in the pH range of 3·5–10·0 The LH activity was monitored in each of the eluted fractions by an in-vitro bioassay and a radioimmunoassay procedure and the profiles of biological activity and immunoreactivity were compared with those of the first IRP of Human Pituitary Luteinizing Hormone for Immunoassay (code no. 68/40).

The overall recovery of the biological activity after electrofocusing of the nine preparations ranged between 75 and 92% (mean 86%) and was higher (P < 0·05) than that of the immunological reactivity which varied between 71 and 94% (mean 79%).

The profiles of the biological activity and immunological reactivity were in close agreement with each other in all preparations. Significant differences were, however, observed in the distribution of various molecular species between the currently used standard and the eight other highly purified preparations.

The ratios of biological activity (B) to immunoreactivity (I) of preparation B and of the three Kabi preparations were significantly higher than those of the other five preparations, both before and after electrofocusing. After electrofocusing, a slight but significant (P < 0·05) rise in the B/I ratios was observed, suggesting that some biologically inactive immunoreactive material was removed during fractionation. All purified preparations lacked the characteristic 'acidic' human LH species which accompanies FSH and which is abundant in the IRP (69/104) and is also present in aqueous extracts of postmenopausal pituitary glands.

A comparison of the electrofocusing profiles of the nine highly purified preparations with those of human LH from plasma and individual pituitary glands revealed marked differences, suggesting that the methods used for the purification of the hormone significantly altered its molecular composition.

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O A Adebanjo
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M Pazianas
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A Zaidi
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V S Shankar
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Z A Bascal
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C G Dacke
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C L-H Huang
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M Zaidi
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Abstract

Prostaglandins exert marked but transient inhibitory effects on bone resorption. The present study examines the effects of prostacyclin (0·15 to 25 μm) on the morphology of freshly disaggregated rat osteoclasts. An area descriptor, p, represented changes in total cell spread area, and a motility descriptor, μ, represented overall changes in cell motility. The application of prostacyclin intercepted the trend of an increasing cell spread area with time and produced a transient reduction of ρ, an R effect. Its magnitude depended upon concentration and was marked at 25 μm prostacyclin. The subsequent recovery (+0·8/min) of ρ at this concentration resembled the persistent spreading seen in the absence of the agonist. There was also a sustained decrease in μ to approximately 60% of its pretreatment value (a Q effect) following the application of 25 μm prostacyclin. The extracellular application of 20 mm [Ca2+] produced a similarly transient cell retraction preceded by a rise of cytosolic [Ca2+], but without a corresponding decrease in μ. In contrast, prostacyclin did not elevate cytosolic [Ca2+], suggesting the triggering of an alternative transduction pathway. A fully reversible retraction together with incomplete quiescence may explain the transience characteristic of the antiresorptive action of prostacyclin.

Journal of Endocrinology (1994) 143, 375–381

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M. Zaidi
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T. J. Chambers
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R. E. Gaines Das
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H. R. Morris
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I. MacIntyre
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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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M. A. Ghatei
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H. K. Datta
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M. Zaidi
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D. Bretherton-Watt
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S. J. Wimalawansa
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I. MacIntyre
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S. R. Bloom
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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.

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B. S. Moonga
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A. S. M. Towhidul Alam
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P. J. R. Bevis
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F. Avaldi
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R. Soncini
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C. L.-H. Huang
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M. Zaidi
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ABSTRACT

It is now established that calcium is a second messenger mediating the action of calcitonin on the osteoclast. We have demonstrated that an increase in the concentration of intracellular free calcium ([Ca2+]i) is associated with (and possibly mediates) the functional effects of calcitonin, including an acute reduction of cell spread area (the R effect) and, in the longer term, a reduction in enzyme release. The present study addresses questions relating to mechanisms of calcitonin action on osteoclast [Ca2+]i. We have used asusuberic(1–7) eel and human calcitonin as agonists, and an indo-1-based dual-emission microspectrofluorimetric method for the measurement of [Ca2+]i in single osteoclasts. Whilst asusuberic(1–7) eel calcitonin caused a biphasic increase in [Ca2+]i, human calcitonin produced only a monophasic [Ca2+]i response of a much lower magnitude. Each biphasic response consisted of a rapid initial transient increase, occurring within seconds of exposure, followed by a sustained increase in [Ca2+]i. The magnitude of the latter response was more variable, but was consistently below the peak value of [Ca2+]i. The sustained phase of the calcitonin effect was abolished in extracellular Ca2+-free medium. This phase is therefore dependent on extracellular [Ca2+] ([Ca2+]e) whilst the rapid transient increase appeared to be dependent on Ca2+ i redistribution. The effects of calcitonin on [Ca2+]i were concentration-dependent, with neither latency nor oscillations. Repetitive 30-s exposures to calcitonin failed to produce subsequent responses. There was a marked concentration-dependent correlation between changes in osteoclast [Ca2+]i and the magnitude of the R effect. Thus the likely components of the biphasic [Ca2+]i response are a rapid redistribution followed by the transmembrane flux of Ca2+. We suggest that the increase in [Ca2+]i may mediate, in part, the inhibitory effect of calcitonin.

Journal of Endocrinology (1992) 132, 241–249

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A. S. M. T. Alam
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C. M. R. Bax
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V. S. Shankar
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B. E. Bax
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P. J. R. Bevis
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C. L.-H. Huang
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B. S. Moonga
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M. Pazianas
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M. Zaidi
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ABSTRACT

Calcitonin is a circulating polypeptide that inhibits bone resorption by inducing both quiescence (Q effect) and retraction (R effect) in osteoclasts. Two structurally related members of the calcitonin gene peptide family, calcitonin gene-related peptide (CGRP) and amylin, inhibit osteoclastic bone resorption selectively via the Q effect. In the present study, we have made measurements of cell spread area in response to the application of amylin, CGRP and a peptide fragment of CGRP, CGRP-(Val8Phe37). We found that, over a wide concentration range (50 pmol/l to 2·5 μmol/l), the selective Q effect agonists did not produce an R effect. Furthermore, the peptides, when used at a 50-fold higher molar concentration than calcitonin, did not antagonize calcitonin-induced cell retraction. Additionally, experiments designed to measure changes in the intracellular free calcium concentration ([Ca2 + ]i) in single osteoclasts revealed that, unlike calcitonin, the non-calcitonin Q effect agonists did not produce a rise in [Ca2+]i. The peptides were also unable to attenuate the peak rise in [Ca2+]i induced by calcitonin. The results support our hypothesis that the inhibitory activity of calcitonin on osteoclastic bone resorption is mediated by two sites which may or may not be part of the same receptor complex. One of these is the classical Q effect site coupled to adenylate cyclase via a cholera toxin-sensitive Gs. This site can be activated by nanomolar concentrations of calcitonin, amylin, CGRP or CGRP-(Val8Phe37). A novel R effect site, possibly coupled via a pertussis toxin-sensitive G protein to a [Ca2+]i elevating mechanism is predicted from this study. The site is highly specific for calcitonin and is not activated, even at micromolar concentrations, by amylin, CGRP or CGRP-(Val8Phe37). Whether or not the two sites are part of the same receptor complex or are two receptor subtypes remains to be determined.

Journal of Endocrinology (1993) 136, 7–15

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