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A Siddiqi, JM Burrin, DF Wood and JP Monson

Hyperthyroidism is associated with increased bone resorption but the mechanisms by which thyroid hormone (T3) affects bone cell metabolism remain unclear. Recently it has been suggested that T3 stimulates osteoclastic resorption indirectly through the release of soluble mediators from osteoblasts. The aim of the present study was to investigate whether the T3-induced increase in bone resorption could be due to the regulation of cytokine production by human osteoblasts (hOb). The effects of T3 (1, 10, 100 nM) and IL-1 beta (100 U/ml) as the positive control were examined on cytokine protein release and mRNA levels in cultured hOb cell lines (MG63, SaOs-2), primary hOb and human bone marrow stromal (hBMS) cells. T3 increased IL-6 and IL-8 mRNA levels as well as IL-6 and IL-8 protein release into the culture media from MG63 and hBMS cells in a time- and dose-dependent manner. The maximal effect on protein release in hBMS cells occurred at 24 h with a dose of T3 10 nM (IL-6 5.5 +/- 1.1-fold above controls; IL-8 3.7 +/- 0.5-fold above controls, P < 0.05). At the same time, mRNA levels in hBMS cells were increased 6.2 +/- 0.8-fold for IL-6 (P < 0.05) and 5.7 +/- 0.8-fold for IL-8 (P < 0.05). Similar results were obtained in MG63 cells but no response was seen in SaOs-2 or hOb cells despite measurable basal production. Nor was there detectable regulation of IL-1 beta, IL-3, IL-11, IL-4 or granulocyte macrophage-colony stimulating factor by T3 in any cell type. In conclusion, T3 increases IL-6 and IL-8 production by MG63 and hBMS cells, suggesting that IL-6 and IL-8 may be T3-regulated genes in osteoblasts.

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Calcium and phosphorus metabolism were studied in 22 patients with spontaneous primary hypothyroidism. Two patients were found to have hypercalcaemia but the mean serum calcium concentration of the group was significantly less than that of control subjects. The renal tubular reabsorption of phosphate was decreased and could be increased to normal with small calcium infusions. The response to calcium deprivation and to infusions of EDTA was abnormal and suggested an impaired ability to mobilize calcium from bone. There was a significant correlation between the defect in calcium mobilization, as judged from the response to EDTA, and the renal tubular reabsorption of phosphate.

In three patients serum parathyroid hormone concentrations, measured by radioimmunoassay, were in the upper part of the normal range.

It is suggested that in patients with hypothyroidism the target cells in bone are less responsive to the effects of parathyroid hormone than normal; as a consequence parathyroid hormone secretion may be increased.

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Isabel Rodríguez-Gómez, Inmaculada Banegas, Rosemary Wangensteen, Andrés Quesada, Rosario Jiménez, Mercedes Gómez-Morales, Francisco O'Valle, Juan Duarte and Félix Vargas

The purpose was to analyse the cardiac and renal capillary density and glomerular morphology resulting from a chronic excess or deficiency of thyroid hormones (THs) in rats. We performed histopathological, morphometrical and immunohistochemical analyses in hypothyroid and hyperthyroid rats to evaluate the density of mesenteric, renal and cardiac vessels at 4 weeks after induction of thyroid disorders. The main angiogenic factors in plasma, heart and kidney were measured as possible mediators of vascular changes. Mesenteric vessel branching was augmented and decreased in hyper- and hypothyroid rats respectively. The numerical density of CD31-positive capillaries was higher in left and right ventricles and in cortical and medullary kidney from both hyper- and hypothyroid rats vs controls. Numbers of podocytes and glomeruli per square millimetre were similar among groups. Glomerular area and percentage mesangium were greater in the hyperthyroid vs control or hypothyroid groups. No morphological renal lesions were observed in any group. Vascularisation of the mesenteric bed is related to TH levels, but an increased capillarity was observed in heart and kidney in both thyroid disorders. This increase may be produced by higher tissue levels of angiogenic factors in hypothyroid rats, whereas haemodynamic factors would predominate in hyperthyroid rats. Our results also indicate that the renal dysfunctions of thyroid disorders are not related to cortical or medullary microvascular rarefaction and that the proteinuria of hyperthyroidism is not secondary to a podocyte deficit. Finally, TH or its analogues may be useful to increase capillarity in renal diseases associated with microvascular rarefaction.

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A Santillo, L Burrone, S Falvo, R Senese, A Lanni and G Chieffi Baccari

The rat Harderian gland (HG) is an orbital gland producing a copious lipid secretion. Recent studies indicate that its secretory activity is regulated by thyroid hormones. In this study, we found that both isoforms of the thyroid hormone receptor (Tr α (Thra) and Tr β (Thrb)) are expressed in rat HGs. Although Thra is expressed at a higher level, only Thrb is regulated by triiodothyronine (T3). Because T3 induces an increase in lipid metabolism in rat HGs, we investigated the effects of an animal's thyroid state on the expression levels of carnitine palmitoyltransferase-1A (Cpt1a) and carnitine palmitoyltransferase-1B (Cpt1b) and acyl-CoA oxidase (Acox1) (rate-limiting enzymes in mitochondrial and peroxisomal fatty acid oxidation respectively), as well as on the mitochondrial compartment, thereby correlating mitochondrial activity and biogenesis with morphological analysis. We found that hypothyroidism decreased the expression of Cpt1b and Acox1 mRNA, whereas the administration of T3 to hypothyroid rats increased transcript levels. Respiratory parameters and catalase protein levels provided further evidence that T3 modulates mitochondrial and peroxisomal activities. Furthermore, in hypothyroid rat HGs, the mitochondrial number and their total area decreased with respect to the controls, whereas the average area of the individual mitochondrion did not change. However, the average area of the individual mitochondrion was reduced by ∼50% in hypothyroid T3-treated HGs, and the mitochondrial number and the total area of the mitochondrial compartment increased. The mitochondrial morphometric data correlated well with the molecular results. Indeed, hypothyroid status did not modify the expression of mitochondrial biogenesis genes such as Ppargc1a, Nrf1 and Tfam, whereas T3 treatment increased the expression level of these genes.

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Renal iodide clearance in rats was reduced rapidly when the animals were fed a protein-depletion diet. If the iodine content of the protein-depletion diet is high, this results in an increase in the serum iodide levels to concentrations in excess of 150 μg./100 ml. Protein-bound iodine was elevated due to the accumulation of iodinated serum albumin. Thyroid hormonal iodoamino acid content was transiently depressed, presumably by the mechanism described by Wolff & Chaikoff (1948). Thyroxine metabolism was not affected except for a change in the partition of thyroxine between liver and serum. There was no evidence for pituitary involvement in the effects of protein depletion on thyroid function.

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T Mano, R Sinohara, Y Sawai, N Oda, Y Nishida, T Mokuno, K Asano, Y Ito, M Kotake, M Hamada, A Nakai and A Nagasaka


To determine how lipid peroxides and free radical scavengers are changed in the brain of hyper- or hypothyroid rats, we examined the behavior of lipid peroxide and free radical scavengers in the cerebral cortex of aged (1·5 years old) rats that had been made hyper- or hypothyroid by the administration of thyroxine or methimazol for 4 weeks. Concentrations of catalase, Mn-superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased in hyperthyroid rats compared with euthyroid rats. Concentrations of total SOD, Cu,Zn-SOD and GSH-PX were increased but that of Mn-SOD was decreased in hypothyroid animals. There were no differences among hyperthyroid, hypothyroid and euthyroid rats in the levels of coenzymes 9 or 10. The concentration of lipid peroxides, determined indirectly by the measurement of thiobarbituric acid reactants, was decreased in hyperthyroid rats but not in hypothyroid rats when compared with euthyroid animals.

These findings suggest that free radicals and lipid peroxides are scavenged to compensate for the changes induced by hyper- or hypothyroidism.

Journal of Endocrinology (1995) 147, 361–365

Free access

A Boelen, J Kwakkel, W M Wiersinga and E Fliers

During illness, changes in thyroid hormone metabolism occur, known as nonthyroidal illness and characterised by decreased serum triiodothyronine (T3) and thyroxine (T4) without an increase in TSH. A mouse model of chronic illness is local inflammation, induced by a turpentine injection in each hind limb. Although serum T3 and T4 are markedly decreased in this model, it is unknown whether turpentine administration affects the central part of the hypothalamus–pituitary–thyroid axis (HPT-axis). We therefore studied thyroid hormone metabolism in hypothalamus and pituitary of mice during chronic inflammation induced by turpentine injection. Using pair-fed controls, we could differentiate between the effects of chronic inflammation per se and the effects of restricted food intake as a result of illness. Chronic inflammation increased interleukin (IL)-1β mRNA expression in the hypothalamus more rapidly than in the pituitary. This hypothalamic cytokine response was associated with a rapid increase in local D2 mRNA expression. By contrast, no changes were present in pituitary D2 expression. TSHβ mRNA expression was altered compared with controls. Comparing chronic inflamed mice with pair-fed controls, both preproTSH releasing hormone (TRH) and D3 mRNA expression in the paraventricular nucleus were significantly lower 48 h after turpentine administration. The timecourse of TSHβ mRNA expression was completely different in inflamed mice compared with pair-fed mice. Turpentine administration resulted in significantly decreased TSHβ mRNA expression only after 24 h while later in time it was lower in pair-fed controls. In conclusion, central thyroid hormone metabolism is altered during chronic inflammation and this cannot solely be attributed to diminished food intake.

Free access

E M de Vries, H C van Beeren, M T Ackermans, A Kalsbeek, E Fliers and A Boelen

A variety of illnesses that leads to profound changes in the hypothalamus–pituitary–thyroid (HPT) are axis collectively known as the nonthyroidal illness syndrome (NTIS). NTIS is characterized by decreased tri-iodothyronine (T3) and thyroxine (T4) and inappropriately low TSH serum concentrations, as well as altered hepatic thyroid hormone (TH) metabolism. Spontaneous caloric restriction often occurs during illness and may contribute to NTIS, but it is currently unknown to what extent. The role of diminished food intake is often studied using experimental fasting models, but partial food restriction might be a more physiologically relevant model. In this comparative study, we characterized hepatic TH metabolism in two models for caloric restriction: 36 h of complete fasting and 21 days of 50% food restriction. Both fasting and food restriction decreased serum T4 concentration, while after 36-h fasting serum T3 also decreased. Fasting decreased hepatic T3 but not T4 concentrations, while food restriction decreased both hepatic T3 and T4 concentrations. Fasting and food restriction both induced an upregulation of liver D3 expression and activity, D1 was not affected. A differential effect was seen in Mct10 mRNA expression, which was upregulated in the fasted rats but not in food-restricted rats. Other metabolic pathways of TH, such as sulfation and UDP-glucuronidation, were also differentially affected. The changes in hepatic TH concentrations were reflected by the expression of T3-responsive genes Fas and Spot14 only in the 36-h fasted rats. In conclusion, limited food intake induced marked changes in hepatic TH metabolism, which are likely to contribute to the changes observed during NTIS.

Free access

R Shinohara, T Mano, A Nagasaka, R Hayashi, K Uchimura, I Nakano, F Watanabe, T Tsugawa, M Makino, H Kakizawa, M Nagata, K Iwase, Y Ishizuki and M Itoh

Free radicals, hydroxyperoxides and H(2)O(2) are all known to damage cell components. This study was designed to compare the concentrations of hydroxyperoxide and free radical scavengers in the cardiac muscles of old rats in the hyper- or hypothyroid condition, to determine whether rates of peroxidation would differ with age, thyroid status, or both. Rats were rendered hyper- or hypothyroid by administration of l-thyroxine or methimazole for 4 weeks. Among the old rats, the lipid peroxide (LPO) concentrations, measured as thiobarbituric acid (TBA) reactants, were significantly greater in the hyperthyroid than in the euthyroid state and the LPO concentrations measured as TBA+Fe(3+) reactants, which may be precursors of LPO, were significantly greater in the hyperthyroid state, whereas in young rats, the LPO concentrations measured by TBA or TBA+Fe(3+) methods did not differ significantly in the hyperthyroid state. In the euthyroid state, the concentration of LPO measured as TBA+Fe(3+) reactants was significantly reduced with age. Xanthine oxidase (XOD) activity also was markedly increased with age, being more pronounced in the hyperthyroid than in the euthyroid state. The Mn and Cu/Zn superoxide dismutase activities were greater in the hyperthyroid than in the euthyroid state. Glutathione peroxidase activity decreased with age in the euthyroid and, particularly, in the hyperthyroid state. Catalase activity was not affected in the old rats. Concentrations of alpha-tocopherol in the old rats were high in the hyperthyroid state and low in the hypothyroid state, whereas the levels of beta- and gamma-tocopherols in these rats were unchanged in both conditions as compared with the euthyroid state findings. Data suggest that the site of free radical generation differs in older rats, with additional shifts in the location of intracellular lipid peroxidation being noted during hyperthyroidism. Thus, as rats age, the reduction of the free radical scavenger system and the increase in LPO and XOD activities might induce myocardial dysfunction.

Free access

B Maiztegui, M I Borelli, M A Raschia, H Del Zotto and J J Gagliardino

β-Cell mass, hexokinase/glucokinase (HK/GK) activity, glucose metabolism and insulin secretion were studied in the islets of rats with fructose-induced insulin resistance (IR). Normal male Wistar rats were fed a standard commercial diet and water without (control, C) or with 10% fructose-rich diet (FRD) for 3 weeks. Blood glucose (strips), triglyceride (commercial kit), and insulin (RIA) levels were measured at the time of death. Glucose-induced insulin release, glucose metabolism (14CO2 and 3H2O production from d-[U-14C]- and d-[5-3H]-glucose) and HK/GK activity (G-6-P production), transcription (RT-PCR), protein expression (Western blot), and cellular compartmentalization were measured in isolated islets (collagenase digestion). FRD rats presented normoglycemia but impaired glucose tolerance, hypertriglyceridemia, hyperinsulinemia, and increased HOMA-IR index. In these rats, β-cell mass decreased significantly by 33%, with a 44% increase in the percentage of apoptotic cells. Glucose-induced insulin release and islet glucose metabolism were higher in FRD rats. While GK activity (total and cytosolic fraction) and protein expression were significantly higher in FRD islets, HK showed no change in any of these parameters. Our results demonstrate that the changes induced by dietary-induced IR upon β-cell function and mass are strongly conditional on the nutrient model used. In our model (intact animals with impaired glucose tolerance), GK activity increases through mechanisms previously shown only in vitro or under highly hyperglycemic conditions. Such an increase plays a pivotal role in the adaptive increased release of insulin in response to IR, even in the presence of marked β-cell mass reduction.