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The regulation of the secretion of calcitonin
BoneandMineral, 16(1992) 182-185
182
Elsevier
BAM00424
The regulationof the secretion of calcitonin
Anthony D. Care Departmentof Biochemistry, UniversityCollege of Wales, AberystwythDyfed, UK
Because of the close anatomical association between the thyroid and parathyroid glands in most mammalian species, unambiguous interpretation of the results of experiments designed to demonstrate the control of calcitonin secretion was not possible until the use of the pig. In this species the thyroid gland contains no parathyroid tissue. This is anatomically separate from the thyroid with its own vascular system. The ultimobranchial body, the source of calcitonin, becomes dispersed within the thyroid gland during embryonic life [l] so that calcitonin is secreted into the thyroid venous blood. In the earlier work, increased secretion of calcitonin was deduced from an acute hypocalcaemic reaction, the interpretation of which was sometimes complicated by the effect of the hypercalcaemic challenge. However, this problem was overcome by isolation in situ of the porcine thyroid gland and quantitative collection of the thyroid venous effluent, followed by the measurement of caicitonin in the plasma by a sensitive bioassay [2]. By this method it was clearly established that there is a linear relationship between the ambient calcium concentration and the secretion rate of calcitonin [3]. A similar relationship was found to exist in birds [4,5]. Unlike parathyroid hormone, the extent of calcitonin storage within its cells of origin is large relative to its secretion rate, so that perfusion experiments lasting several hours can be undertaken without exhaustion of stored calcitonin. Moreover, only 30% of the calcitonin secreted from the pig thyroid gland in response to hypercalcaemia represents de novo protein synthesis [5]. It was also shown that hypercalcaemia stimulated the synthesis of calcitonin as well as its release from the C cells. Addition of strontium or magnesium ions to blood perfusing the thyroid gland also leads to stimulation of calcitonin secretion but the effect of magnesium is not as great as that of an equimolar increase in calcium ion concentration [6]. The use of the calcium ionophore A23187 [7], calcium channel blockers and calcium channel openers [8] has clearly indicated that it is the calcium ion concentration within the C cell that determines the rate of secretion of calcitonin. This secretion is modulated positively by the paracrine factor calcitonin gene related peptide [9] and 0169~6009/92/$05.00 @ 1992Elsevier Science PublishersB.V. (BiomedicalDivision)
183 negatively by another paracrine factor, somatostatin [lo]. A putative increase in the calcium ion concentration within the porcine C cells, caused by the use of block the stimulatory action of calmodulin on the outwardly directed Ca pump activated by Ca/Mg ATP-ase, led to an increase in calcitonin rate in the pig [111. Enhanced calcitonin release can be blocked by cyanide and stimulated by cyclic AMP [ 121. The actions of glucagon are mediated through activation of adenyl cyclase at its target organs. It was soon shown that glucagon concentrations as low as 1.4 nM are capable of stimulating the secretion of calcitonin from pig thyroid gland so long as rapid destruction of the added glucagon was prevented by the addition of aprotinin [ 121. Enteroglucagon also stimulates the secretion of calcitonin [ 131.Beta adrenergic agents also stimulate the secretion of calcitonin by activation of C cell adenyl cyclase [ 121. Because of a structural similarity between glucagon and secretin, the latter was tested for activity as a calcitonin secretagogue. The initial preparation used was impure, containing pancreozymin, and stimulated calcitonin secretion whereas pure secretin was without effect [14]. It was then shown that pure pancreozymin was a potent calcitonin secretagogue and that this activity was contained in the C-terminal octapeptide, the C-terminal tetrapeptide of which is shared with gastrin (and pentagastrin) and caerulein. These three compounds all stimulated calcitonin secretion in vivo [15,16]. This stimulatory effect is also via activation of C cell adenyl
Sensitisobon of tnyrod C-cells to Co++ by pentagastrin
Time (hrs)
Fig. 1. Sensitisation of the thyroid C cells in a pig to a hypercalcaemic challenge following prior exposure to a minimal concentration of pentagastrin. A pig thyroid gland was isolated in situ and perfused with autologous arterial blood under controlled conditions and the calcitonin concentrations were measured in the thyroid venous outflow by bioassay.
184
leading to a sensitisation of the C cells to a hypercalcaemic challenge (Fig. 1). Release of endogenous hormone (e.g. gastrin by intragastric meat extract, glytine or distention; pancreozymin by intraduodenal fat and enteroglucagon by intraduodenal glucose) also increases the secretion rate of calcitonin in pigs [13], thus supporting the concept that calcitonin might play a role in the control of postprandial hypercalcaemia [17]. It also accounts for the observations that: 1) administration of a small amount of calcium chloride into the jejunum, insufficient to alter the peripheral calcium concentration, nevertheless brought about an increase in the secretion of calcitonin [ 181;and 2) feeding intact young pigs following a fast leads to a hypocalcaemic response whereas if the pigs had first been recently thyroidectomized a hypercalcaemic response occurred [ 131. In contrast to mammals, caerulein was without effect on the secretion rate of calcitonin in the goose. Also, unlike the mammalian thyroid C cells, the avian ultimobranchial body is well innervated by the vagus and electrical stimulation of the peripheral portion of a ligated vagus nerve resulted in stimulation of calcitonin secretion [ 191. Perhaps the stimulus for calcitonin secretion in birds durmg normocalcaemia is neural rather than hormonal. The plasma concentration of calcitonin in fetal lambs is higher than in the mother because such lambs are hypercalcaemic. However, the calcitonin secretion rates are similar to those found in adult sheep, suggesting that the metabolic clearance rate of calcitonin is lower in the fetus than in the adult [20]. This may indicate a role for calcitonin in the high rate of bone accretion characteristic of the fetal lamb, cyclase,
References 1 Badertscher JA. The fate of the ultimobranchial bodies in the pig (Sus scrofa). Amer J Anat 1918;23:89-122. 2 Cooper CW. Hirsch PF, Toverud SU, Munson PL. An improved method for the bioassay of cakitonin. Endocrinology 1%7;81:610-616. 3 Care AD, Cooper CW, Duncan T, Orimo H. A study of thyrocalcitonin secretion by direct measurement of in vivo secretion rates in pigs. Endocrinology 1968;83:161-169. 4 Ziegler R, Telim, Pfeiffer EF. The secretion of calcitonin by the perfused ultimobranchial gland of the hen. Horm Metab Res 1969;1:39-40. 5 Care AD, Bates RFL. Control of secretion of parathyroid hormone and calcitonin in mammals and birds. Gen Comp Endocrin 1972;3:448-458. 6 Care AD, Beil NH, Bates RFL, The effects of hypermagnesaemia on calcitonin secretion in vlvo. J Endocrinoll97l;Sl:381-386. 7 Pento JT. Influence of the calcium ionophores Al23187 and X537A on calcitonin secretion from the isolated perfused porcine thyroid. Molec Cell Endocrinoll986;45:71-75. 8 Cooper CW, Borosky SA, Farreii PE, Steinsiarrd OS. Effectsof tbz calcium channel artivatnr BAYK-8644 on in vitro secretion of calcitonin and parathyroid hormone. Endocrinology 1986:118:545-549. 9 Cooper CW, McPherson MB, Seitz PK, Greetey GH, Abbas SK, Pickard DW, Care AD. Stimulation of calcitonin secretion in the pig by calcitonin gene-related peptide. Bone Miner 1991;12:73-79. 10 Lineham WM, Cooper CW, Bolman RM, Wells SA. Inhibition of in vivo secretion of calcitonin in the pig by somatostatin. Endocrinology 1979;104:1662-1607.
185 11 Abbas SK, Care AD. The involvement of calmodulin in the secretion of calcitonin from the porcine thyroid gland. Horm Metab Res 1988;29:264-266. 12 Care AD, Bates RFL, Gitelman HJ. A possible role for the adenyl cylcase system in calcitonin release. J Endocrinol1970;48: 115. 13 Swaminathan R, Bates RFL, Bloom SR, Ganguli PC, Care AD. The relationship between food, gastro-intestinal hormones and calcitonin secretion. J Endocrinol1973;59:217-230. 14 Care AD. The effects of pancreozymin and secretin on calcitonin release. Fed Proc 1970;29:253. 15 Care AD, Bruce JB, Boelkins J, Kenny AD, Conaway H, Anast CS. The role of pancreozymin-cholecystokinin and structurally related compounds as calcitonin secretagogues. Endocrinology 1971;89:262-271. 16 Cooper CW, Schwesinger WH, Ontjes DA, Mahgoub AM, Munson PL. Stimulation of secretion of pig thyrocalcitonin by gastrin and gastro-intestinal secretagogues. In: Taylor S, ed. Endocrinology. Amsterdam: Excerpta Medica Foundation. 1971;6066. 17 Gray TK, Munson PL, Thyrocalcitonin: evidence for physiological function. Sci NY 1969;166:512-513. 18 Munson PL, Cooper CW, Gray TK, Hundley JD, Mahgoub AM. Physiological importance of thyrocalcitonin. In: Nichols CJ, Wasserman RH, eds. Cellular Mechanisms for Calcium Transfer and Homeostasis. New York: Academic Press, 1971;404-420. 19 Care AD, Bates RFL. Calcitonin secretion in the goose associated with vagal stimulation. J Endocrino1 1974;57:43-44. 20 Garel JM, Care AD, Barlet JP. A radioimmunoassay for ovine calcitonin: an evaluation of calcitonin secretion during gestation, lactation and foetal life. J Endocrinol1974;62:497-509.
182
Elsevier
BAM00424
The regulationof the secretion of calcitonin
Anthony D. Care Departmentof Biochemistry, UniversityCollege of Wales, AberystwythDyfed, UK
Because of the close anatomical association between the thyroid and parathyroid glands in most mammalian species, unambiguous interpretation of the results of experiments designed to demonstrate the control of calcitonin secretion was not possible until the use of the pig. In this species the thyroid gland contains no parathyroid tissue. This is anatomically separate from the thyroid with its own vascular system. The ultimobranchial body, the source of calcitonin, becomes dispersed within the thyroid gland during embryonic life [l] so that calcitonin is secreted into the thyroid venous blood. In the earlier work, increased secretion of calcitonin was deduced from an acute hypocalcaemic reaction, the interpretation of which was sometimes complicated by the effect of the hypercalcaemic challenge. However, this problem was overcome by isolation in situ of the porcine thyroid gland and quantitative collection of the thyroid venous effluent, followed by the measurement of caicitonin in the plasma by a sensitive bioassay [2]. By this method it was clearly established that there is a linear relationship between the ambient calcium concentration and the secretion rate of calcitonin [3]. A similar relationship was found to exist in birds [4,5]. Unlike parathyroid hormone, the extent of calcitonin storage within its cells of origin is large relative to its secretion rate, so that perfusion experiments lasting several hours can be undertaken without exhaustion of stored calcitonin. Moreover, only 30% of the calcitonin secreted from the pig thyroid gland in response to hypercalcaemia represents de novo protein synthesis [5]. It was also shown that hypercalcaemia stimulated the synthesis of calcitonin as well as its release from the C cells. Addition of strontium or magnesium ions to blood perfusing the thyroid gland also leads to stimulation of calcitonin secretion but the effect of magnesium is not as great as that of an equimolar increase in calcium ion concentration [6]. The use of the calcium ionophore A23187 [7], calcium channel blockers and calcium channel openers [8] has clearly indicated that it is the calcium ion concentration within the C cell that determines the rate of secretion of calcitonin. This secretion is modulated positively by the paracrine factor calcitonin gene related peptide [9] and 0169~6009/92/$05.00 @ 1992Elsevier Science PublishersB.V. (BiomedicalDivision)
183 negatively by another paracrine factor, somatostatin [lo]. A putative increase in the calcium ion concentration within the porcine C cells, caused by the use of block the stimulatory action of calmodulin on the outwardly directed Ca pump activated by Ca/Mg ATP-ase, led to an increase in calcitonin rate in the pig [111. Enhanced calcitonin release can be blocked by cyanide and stimulated by cyclic AMP [ 121. The actions of glucagon are mediated through activation of adenyl cyclase at its target organs. It was soon shown that glucagon concentrations as low as 1.4 nM are capable of stimulating the secretion of calcitonin from pig thyroid gland so long as rapid destruction of the added glucagon was prevented by the addition of aprotinin [ 121. Enteroglucagon also stimulates the secretion of calcitonin [ 131.Beta adrenergic agents also stimulate the secretion of calcitonin by activation of C cell adenyl cyclase [ 121. Because of a structural similarity between glucagon and secretin, the latter was tested for activity as a calcitonin secretagogue. The initial preparation used was impure, containing pancreozymin, and stimulated calcitonin secretion whereas pure secretin was without effect [14]. It was then shown that pure pancreozymin was a potent calcitonin secretagogue and that this activity was contained in the C-terminal octapeptide, the C-terminal tetrapeptide of which is shared with gastrin (and pentagastrin) and caerulein. These three compounds all stimulated calcitonin secretion in vivo [15,16]. This stimulatory effect is also via activation of C cell adenyl
Sensitisobon of tnyrod C-cells to Co++ by pentagastrin
Time (hrs)
Fig. 1. Sensitisation of the thyroid C cells in a pig to a hypercalcaemic challenge following prior exposure to a minimal concentration of pentagastrin. A pig thyroid gland was isolated in situ and perfused with autologous arterial blood under controlled conditions and the calcitonin concentrations were measured in the thyroid venous outflow by bioassay.
184
leading to a sensitisation of the C cells to a hypercalcaemic challenge (Fig. 1). Release of endogenous hormone (e.g. gastrin by intragastric meat extract, glytine or distention; pancreozymin by intraduodenal fat and enteroglucagon by intraduodenal glucose) also increases the secretion rate of calcitonin in pigs [13], thus supporting the concept that calcitonin might play a role in the control of postprandial hypercalcaemia [17]. It also accounts for the observations that: 1) administration of a small amount of calcium chloride into the jejunum, insufficient to alter the peripheral calcium concentration, nevertheless brought about an increase in the secretion of calcitonin [ 181;and 2) feeding intact young pigs following a fast leads to a hypocalcaemic response whereas if the pigs had first been recently thyroidectomized a hypercalcaemic response occurred [ 131. In contrast to mammals, caerulein was without effect on the secretion rate of calcitonin in the goose. Also, unlike the mammalian thyroid C cells, the avian ultimobranchial body is well innervated by the vagus and electrical stimulation of the peripheral portion of a ligated vagus nerve resulted in stimulation of calcitonin secretion [ 191. Perhaps the stimulus for calcitonin secretion in birds durmg normocalcaemia is neural rather than hormonal. The plasma concentration of calcitonin in fetal lambs is higher than in the mother because such lambs are hypercalcaemic. However, the calcitonin secretion rates are similar to those found in adult sheep, suggesting that the metabolic clearance rate of calcitonin is lower in the fetus than in the adult [20]. This may indicate a role for calcitonin in the high rate of bone accretion characteristic of the fetal lamb, cyclase,
References 1 Badertscher JA. The fate of the ultimobranchial bodies in the pig (Sus scrofa). Amer J Anat 1918;23:89-122. 2 Cooper CW. Hirsch PF, Toverud SU, Munson PL. An improved method for the bioassay of cakitonin. Endocrinology 1%7;81:610-616. 3 Care AD, Cooper CW, Duncan T, Orimo H. A study of thyrocalcitonin secretion by direct measurement of in vivo secretion rates in pigs. Endocrinology 1968;83:161-169. 4 Ziegler R, Telim, Pfeiffer EF. The secretion of calcitonin by the perfused ultimobranchial gland of the hen. Horm Metab Res 1969;1:39-40. 5 Care AD, Bates RFL. Control of secretion of parathyroid hormone and calcitonin in mammals and birds. Gen Comp Endocrin 1972;3:448-458. 6 Care AD, Beil NH, Bates RFL, The effects of hypermagnesaemia on calcitonin secretion in vlvo. J Endocrinoll97l;Sl:381-386. 7 Pento JT. Influence of the calcium ionophores Al23187 and X537A on calcitonin secretion from the isolated perfused porcine thyroid. Molec Cell Endocrinoll986;45:71-75. 8 Cooper CW, Borosky SA, Farreii PE, Steinsiarrd OS. Effectsof tbz calcium channel artivatnr BAYK-8644 on in vitro secretion of calcitonin and parathyroid hormone. Endocrinology 1986:118:545-549. 9 Cooper CW, McPherson MB, Seitz PK, Greetey GH, Abbas SK, Pickard DW, Care AD. Stimulation of calcitonin secretion in the pig by calcitonin gene-related peptide. Bone Miner 1991;12:73-79. 10 Lineham WM, Cooper CW, Bolman RM, Wells SA. Inhibition of in vivo secretion of calcitonin in the pig by somatostatin. Endocrinology 1979;104:1662-1607.
185 11 Abbas SK, Care AD. The involvement of calmodulin in the secretion of calcitonin from the porcine thyroid gland. Horm Metab Res 1988;29:264-266. 12 Care AD, Bates RFL, Gitelman HJ. A possible role for the adenyl cylcase system in calcitonin release. J Endocrinol1970;48: 115. 13 Swaminathan R, Bates RFL, Bloom SR, Ganguli PC, Care AD. The relationship between food, gastro-intestinal hormones and calcitonin secretion. J Endocrinol1973;59:217-230. 14 Care AD. The effects of pancreozymin and secretin on calcitonin release. Fed Proc 1970;29:253. 15 Care AD, Bruce JB, Boelkins J, Kenny AD, Conaway H, Anast CS. The role of pancreozymin-cholecystokinin and structurally related compounds as calcitonin secretagogues. Endocrinology 1971;89:262-271. 16 Cooper CW, Schwesinger WH, Ontjes DA, Mahgoub AM, Munson PL. Stimulation of secretion of pig thyrocalcitonin by gastrin and gastro-intestinal secretagogues. In: Taylor S, ed. Endocrinology. Amsterdam: Excerpta Medica Foundation. 1971;6066. 17 Gray TK, Munson PL, Thyrocalcitonin: evidence for physiological function. Sci NY 1969;166:512-513. 18 Munson PL, Cooper CW, Gray TK, Hundley JD, Mahgoub AM. Physiological importance of thyrocalcitonin. In: Nichols CJ, Wasserman RH, eds. Cellular Mechanisms for Calcium Transfer and Homeostasis. New York: Academic Press, 1971;404-420. 19 Care AD, Bates RFL. Calcitonin secretion in the goose associated with vagal stimulation. J Endocrino1 1974;57:43-44. 20 Garel JM, Care AD, Barlet JP. A radioimmunoassay for ovine calcitonin: an evaluation of calcitonin secretion during gestation, lactation and foetal life. J Endocrinol1974;62:497-509.