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M Abe, N Akeno, S Ohida, and N Horiuchi

We investigated the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 9-cis-retinoic acid (9cRA) on parathyroid hormone-related protein (PTHrP) production and its mRNA expression by the human oral squamous carcinoma cell line (HSC-3). The major transcript of PTHrP was 1.5 kb in human HSC-3 cells. In the presence and absence of serum, 1,25(OH)2D3 produced dose-dependent inhibition of PTHrP gene expression and secretion. Significant inhibition by 1,25(OH)2D3 in the presence of serum was observed at 10(-10) M for mRNA expression and 10(-8) M for secretion, whereas under serum-free conditions, 1,25(OH)2D3 significantly suppressed PTHrP mRNA expression at 10(-10) M and secretion at 10(-9) M. Thus the remainder of the experiments were performed under serum-free conditions. After 24 h of incubation, 9cRA decreased dose-dependently PTHrP mRNA expression and PTHrP secretion. Addition of 10(-7) M 1,25(OH)2D3 or 10(-7) M 9cRA to HSC-3 cells significantly suppressed PTHrp transcription within 1 h and the PTHrP secretion within 12 h. Maximal suppression of mRNA expression was maintained for 12-48 h. 9cRA caused a continuous decrease in PTHrP secretion for up to 48 h, whereas the inhibition of secretion by 1,25(OH)2D3 was transient and abolished by 48 h. Neither 1,25(OH)2D3 nor 9cRA altered the stability of PTHrP mRNA. The inhibitory effect of 1,25(OH)2D3 and 9cRA on PTHrP mRNA expression was additive, whereas no additive effect was observed with regard to PTHrP secretion. These results indicate that 1,25(OH)2D3 and 9cRA suppressed PTHrP production and mRNA expression in oral squamous cancer cells, and suggest that transcriptional suppression may act through binding of the heterodimer (vitamin D receptor-retinoid X receptor) to negatively responsive elements of the PTHrP gene.

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Department of Animal Physiology and Nutrition, University of Leeds, Leeds, LS2 9JT, *Department of Medicine, The Middlesex Hospital, London, WIN 8AA and †Institut de Rhumatologie, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75674 Paris, France

(Received 16 March 1978)

1,25-Dihydroxycholecalciferol (1,25-DHCC) is the principal biologically active metabolite of vitamin D, but under certain conditions, other dihydroxylated forms of vitamin D in the circulation may be important. One of these is 25,26-dihydroxycholecalciferol (25,26-DHCC), for which the biological significance and the tissue of origin are not yet known. It has been reported that 25,26-DHCC increases active intestinal transport of calcium in calcium-deficient rats, but has no effect in calcium-replete or nephrectomized animals (Miravet, Redel, Care, Queille & Bordier, 1976). Its biological activity is probably dependent upon previous renal hydroxylation at position 1 of the molecule to form 1,25,26-trihydroxycholecalciferol (Lam, Schnoes & DeLuca, 1975). It has been calculated that the concentration of 25,26-DHCC

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Gross deformities appeared in Xenopus laevis maintained for about 2 yr. under laboratory conditions on a diet containing no live food. Radiographs of the affected animals revealed defective calcification of the skeleton. All animals bred in the colony were defective, and only the original adults taken from the wild had normal bones. A description of the different types of skeleton found, and later produced experimentally, is given. An analysis of the conditions under which the defects became manifest showed X. laevis to be very susceptible to lack of vitamin D. Calcification in this species is greatly affected by the nature of the basal food. Normal bones are formed when the toads are fed on a diet of rabbit liver (or ox liver) supplemented with cod-liver oil and calcium. Horse liver is toxic, causing a depression of growth and a failure of calcification even with the supplements. With guinea-pig muscle a far larger supplement of vitamin D is required to prevent the development of general calcium deficiency and to permit normal bone formation. The failure of calcification is identified as rickets with osteoporosis and its relation to these diseases in other species is discussed.

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HH Conaway, D Grigorie, and UH Lerner

Differential effects on in vitro bone resorption were observed when the glucocorticoids, hydrocortisone and dexamethasone, were added to neonatal mouse calvariae treated with either parathyroid hormone (PTH), 1,25(OH)2-vitamin D3, all trans-retinoic acid (t-RA), or prostaglandin E2 (PGE2). Bone resorption was assessed by analyzing either the release of 45Ca from [45Ca]CaCl2 prelabeled calvarial bones or the release of 3H from [3H]proline prelabeled calvariae. At PGE2 concentrations of 3 x 10(-8) and 3 x 10(-7) mol/l, co-treatment with either 10(-6) mol/l dexamethasone or 10(-6) mol/l hydrocortisone caused additive 45Ca release from neonatal mouse calvariae. In contrast, synergistic release from mouse calvarial bones of both 45Ca and 3H was found after either 10(-6) mol/l hydrocortisone or 10(-6) mol/l dexamethasone was combined with 3 x 10(-11) mol/l PTH treatment for 120 h. Dose-response studies indicated that the synergistic stimulation of 45Ca release from neonatal mouse calvariae by glucocorticoids and PTH could be elicited at glucocorticoid concentrations of 10(-8) to 10(-6) mol/l and at PTH concentrations of 10(-11) to 10(-9) mol/l. Progesterone and RU 38486 (a derivative of 19-nortestosterone with antiglucocorticoid activity) blocked the synergism noted with glucocorticoid and PTH co-treatment, suggesting that interaction between the steroids and PTH was dependent on glucocorticoid receptor interaction. Addition of either 10(-6) mol/l hydrocortisone or 10(-6) mol/l dexamethasone to neonatal mouse calvariae treated with 1,25(OH)2-vitamin D3 (10(-11) and 10(-10) mol/l) also resulted in synergistic stimulation of 45Ca release. In contrast to these observations, the stimulatory effect of t-RA (10(-8) mol/l) on 45Ca release from calvarial bones was abolished in the presence of 10(-6) mol/l dexamethasone. These results suggest that an important role of glucocorticoids may be to synergistically potentiate bone resorption stimulated by PTH and 1,25(OH)2-vitamin D3, but indicate an opposing interaction between the glucocorticoids and bone resorptive retinoids.

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K Fuller, JM Owens, and TJ Chambers

It is believed that parathyroid hormone (PTH) increases the resorptive activity of pre-existing osteoclasts through a primary interaction with cells of the osteoblastic lineage. Much less is known, however, of the mechanisms by which PTH induces osteoclast formation. It is known that osteoclast formation occurs through a contact-dependent interaction between stromal cells and haemopoietic precursors, but it is not known whether PTH acts on stromal cells or precursors to induce osteoclast formation. To address this issue, we compared the ability of haemopoietic cultures to generate osteoclasts, identified as calcitonin receptor positive (CTRP) cells, and to resorb bone in response to PTH and 1,25(OH)2 vitamin D3 (1,25(OH)2D3). We found that when murine haemopoietic tissues were incubated at densities sufficiently high to support haemopoiesis, both PTH and 1,25(OH)2D3 induced bone resorption in bone marrow cells, but in cultures of haemopoietic spleen only 1,25(OH)2D3 induced CTRP cells, and neither hormone induced bone resorption. To determine whether these differences were attributable to differences in stromal cells or haemopoietic precursors, lower densities of haemopoietic spleen cells were incubated on osteoblastic (UMR 106), splenic or bone marrow stromal cells. We found that the behaviour of the cocultures reflected the characteristics and origin of the stromal cells. Thus, the ability of both osteoblastic and splenic stromal cells to induce CTRP cells with 1,25(OH)2D3, while only osteoblastic cells induced osteoclasts with PTH, from the same precursors, suggests that the ability of PTH to induce osteoclastic differentiation cannot be attributed to a hormonal action on osteoclast precursors, but depends on a response in stromal cells.

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J. P. Barlet, M.-J. Davicco, and V. Coxam


The influence of synthetic parathyroid hormone related peptide (PTHrp) fragments on placental transfer of Ca was studied in four groups of four single ovine fetuses fitted with catheters chronically implanted into their left jugular vein (for injections) and carotid artery (for blood sampling), and used between days 104 and 118 of gestation. The first group received PTHrp(1–34), the second PTHrp(107-138), the third bovine PTH(1–34), and the last (control) group was injected with solvent alone. Each peptide (6 nmol/fetus per day) was injected i.v. three times per day from day 105 until day 116 of gestation. Placental Ca transfer (mmol/24 h per kg fetal wt) from the dam to the fetus was not different in control fetuses 7·1±0·6) and those given PTHrp(107–138) (7·2±0·5), but it was significantly increased by bovine PTH(1–34) (8·6±0·4; P < 0·05) and by PTHrp(1–34) (10·1±0·3; P < 0·01). Both peptides also significantly increased plasma concentrations of 1,25 dihydroxy-vitamin D3 (1,25-(OH)2D). These results indicate that PTHrp(1–34) can stimulate placental Ca transfer by increasing 1,25-(OH)2D synthesis, but also possibly by acting directly upon the placenta.

Journal of Endocrinology (1990) 127, 33–37

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H. M. Docherty and D. A. Heath

Over the past years the explanation of the hypercalcaemia associated with malignancy has changed repeatedly. Theories have come and gone and, in some cases, come again. The search for new hypercalcaemic factors is gaining momentum and major new breakthroughs seem imminent.

The original explanation of the hypercalcaemia of malignancy was that it was due to bone metastases physically causing the release of calcium from bone. This simple theory, though widely believed, was not supported by any evidence. Many patients with extensive bone disease had normal serum calcium values, many were hypercalcaemic in the absence of bone metastases, and certain malignancies had high or low incidences of hypercalcaemia despite similar rates of bone metastases, c.f. squamous cell and small cell carcinoma of the lung. That certain malignancies might produce a humoral factor was suggested by the work of Gordan, Cantino, Erhardt et al. (1966) who claimed to have isolated vitamin D-like

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E. M. W. Maunder, A. V. Pillay, C. Chapman, and A. D. Care


Insulin-induced hypoglycaemia in the pig elicited sharp increases in the plasma concentrations of vitamin D-dependent calcium-binding protein (CaBP) and cortisol and a decrease in plasma inorganic phosphate. Glucose infusion following insulin administration abolished the increases in plasma CaBP and cortisol in response to insulin and reduced the hypophosphataemia. The percentage increases in plasma CaBP and cortisol in response to insulin-induced hypoglycaemia were reduced when the pigs were fed a low-calcium diet, but the hypophosphataemic response was similar.

We conclude that insulin-induced hypoglycaemia leads to increased plasma CaBP in pigs fed a normal calcium diet, which is associated with the hypoglycaemia rather than being a direct effect of insulin. We therefore suggest that plasma CaBP may represent more than a mere uncontrolled leak from its sites of storage.

J. Endocr. (1986) 109, 101–106

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Department of Physiology and Biochemistry, The University, Southampton, SO9 3TU

(Received 22 February 1975)

In a preliminary experiment with thyroidectomized rats Lewis, Rafferty, Shelley & Robinson (1971) showed that calcitonin (CT) protects the skeleton from excessive resorption during pregnancy and lactation, and Barlet & Garel (1975) made similar observations with goats. The object of the present work was to seek confirmation of this effect and to investigate a possible role for vitamin D in the action of CT.

Over a period of 2 weeks the parathyroid glands of female Wistar rats, initially 7 weeks of age, were removed under a dissecting microscope, cleaned of extraneous tissue and homotransplanted to the thigh muscle. Approximately 2 weeks after the operation the fasting plasma calcium level was determined and those animals with a concentration of 2·4 mmol/l or less were rejected on the assumption that the transplants had not been successful. The remaining

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The absorption of calcium from duodenal and jejunal segments of the small intestine was studied in rats using an in-vivo loop technique. Previous parathyroidectomy decreased calcium absorption from both segments in rats fed a normal diet. Reduced calcium transport was greater in rats fed a calcium-deficient diet after parathyroidectomy. The slower clearance of radioactive calcium from the lumen of the intestine was not due to increased endogenous calcium excretion. Thyroidectomy, either alone or combined with parathyroidectomy, decreased calcium absorption but the effect of thyroidectomy alone requires further study. The decrease in calcium absorption after removal of the parathyroids was minimal or absent when the animals were fed a high calcium, low phosphorus, vitamin D-deficient diet or fasted 48 hr. before the experiment.