Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormones influence growth and differentiation of bone cells. In vivo and in vitro data indicate their importance for development and maintenance of the skeleton. Triiodothyronine (T3) inhibits proliferation and accelerates differentiation of osteoblasts. We studied the regulatory effect of T3 on markers of proliferation as well as on specific markers of the osteoblastic phenotype in cultured MC3T3-E1 cells at different time points. In parallel to the inhibitory effect on proliferation, T3 down-regulated histone H4 mRNA expression. Early genes (c-fos/c-jun) are highly expressed in proliferating cells and are down-regulated when the cells switch to differentiation. When MC3T3-E1 cells are cultured under serum-free conditions, basal c-fos/c-jun expressions are nearly undetectable. Under these conditions, c-fos/c-jun mRNAs can be stimulated by EGF, the effect of which is attenuated to about 46% by T3. In addition, T3 stimulated the expression at the mRNA and protein level of osteocalcin, a marker of mature osteoblasts and alkaline phosphatase activity. All these effects were more pronounced when cells were cultured for more than 6 days. These data indicate that T3 acts as a differentiation factor in osteoblasts by influencing the expression of cell cycle-regulated, of cell growth-regulated, and of phenotypic genes.
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PMID:Triiodothyronine, a regulator of osteoblastic differentiation: depression of histone H4, attenuation of c-fos/c-jun, and induction of osteocalcin expression. 935 83

Thyroid hormones (T3 and T4) regulate bone development, growth, and turnover. Studies have suggested that different skeletal sites respond differently to thyroid hormones. Therefore, we examined the in vitro T3 responsiveness of cells committed to the osteoblast lineage as a function of skeletal location. Bone marrow cells derived from female rat femurs and vertebrae were cultured using conditions that induce osteogenic differentiation. Cells from both sites formed mineralized bone nodules in primary and secondary culture. In femoral cultures, collagen type I (coll I) and osteocalcin (OC) messenger RNA (mRNA) levels increased from the earliest time point examined (day 3) to a maximum on day 12 and thereafter declined to undetectable levels. T3 increased both OC and coll I mRNA, resulting in a continuous expression throughout the culture period. Insulin-like growth factor I (IGF-I) gene expression was detected at very low levels by Northern analysis of femoral total RNA, and T3 only marginally enhanced IGF-I mRNA levels. In vertebral cultures, OC and coll I mRNA levels also increased with time in culture, but remained expressed throughout the culture period. OC and coll I mRNA levels were not markedly altered in response to T3. In contrast to femoral cells, IGF-I gene expression was easily visualized in Northern blots from untreated vertebral cultures and was markedly increased by the addition of T3. The continuous presence of T3 (10(-7) M) in the medium for 18 days caused a marked decrease in the number of alkaline phosphatase-positive colonies formed in femoral secondary cultures, but only a slight decrease in the number in vertebral cultures. In addition, short term (6 days) exposure to T3 (10(-7) M) at the beginning of the culture period decreased alkaline phosphatase activity in femoral cultures, but not in vertebral cultures. These findings indicate that there are skeletal site-dependent differences in the in vitro responses of cells of the osteoblastic lineage to thyroid hormone.
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PMID:Thyroid hormone excess increases insulin-like growth factor I transcripts in bone marrow cell cultures: divergent effects on vertebral and femoral cell cultures. 956 68

The authors reported a twelve year and four-month old girl who had prolonged fever for 2 weeks. Physical examination revealed a painless enlarged thyroid gland with firm consistency. Hyperparathyroidism was suspected because of hypercalcemia, hypophosphatemia, high level of serum alkaline phosphatase, and decreased density of long bones. Thyroid scan showed a cold nodule of the left upper lobe which subsequently proved to be a medullary thyroid carcinoma by high serum thyrocalcitonin level and pathological examination. Her 24-hour urinary vanillyl mandelic acid was in the normal range, and abdominal ultrasonography demonstrated normal adrenal glands. Multiple endocrine neoplasia type IIa (MEN IIa) was diagnosed by medullary thyroid carcinoma and hyperparathyroidism. However, the fully developed syndrome is characterized by the combined occurrence of medullary thyroid carcinoma, primary hyperparathyroidism, and pheochromocytomas. This syndrome is a rare, complex, and potentially lethal disease so early recognition and family screening are very important.
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PMID:Multiple endocrine neoplasia type IIa: a case report. 980 71

Thyroid hormone (TH) responsive genes can be both positively and negatively regulated by TH through receptors (TR) alpha and beta expressed in most body tissues. However, their relative roles in the regulation of specific gene expression remain unknown. The TR beta knockout mouse, which lacks both TR beta1 and TR beta2 isoforms, provides a model to examine the role of these receptors in mediating TH action. TR beta deficient (TR beta-/-) mice that show no compensatory increase in TR alpha, and wild-type (TR beta+/+) mice of the same strain were deprived of TH by feeding them a low iodine diet containing propylthiouracil, and were then treated with supraphysiological doses of L-T3 (0.5, 5.5, and 25 microg/day/mouse). TH deprivation alone increased the serum cholesterol concentration by 25% in TR beta+/+ mice and reduced it paradoxically by 23% in TR beta-/- mice. TH deprivation reduced the serum alkaline phosphatase (AP) concentration by 31% in TR beta+/+ mice but showed no change in the TR beta-/- mice. Treatment with L-T3 (0.5 to 25 microg/mouse/day) caused a 57% decrease in serum cholesterol and a 231% increase in serum AP in the TR beta+/+ mice. The TR beta-/- mice were resistant to the L-T3 induced changes in serum cholesterol and showed increase in AP only with the highest L-T3 dose. Basal heart rate (HR) in TR beta-/- mice was higher than that of TR beta+/+ mice by 11%. HR and energy expenditure (EE) in both TR beta+/+ and TR beta-/- mice showed similar decreases (49 and 46%) and increases (49 and 41%) in response to TH deprivation and L-T3 treatment, respectively. The effect of TH on the accumulation of messenger RNA (mRNA) of TH regulated liver genes was also examined. TH deprivation down regulated spot 14 (S14) mRNA and showed no change in malic enzyme (ME) mRNA in both TR beta+/+ and TR beta-/- mice. In contrast treatment with L-T3 produced an increase in S14 and ME but no change in TR beta-/- mice. From these results, it can be concluded that regulation of HR and EE are independent of TR beta. With the exception of serum cholesterol concentration and liver ME mRNA accumulation, all other markers of TH action examined during TH deprivation exhibited the expected responses in the absence of TR beta. Thus, as previously shown for serum TSH, TR beta is not absolutely necessary for some changes typical of hypothyroidism to occur. In contrast, except for HR and EE, the full manifestation of TH-mediated action required the presence of TR beta.
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PMID:Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice. 983 32

In this cross-sectional study, we evaluated 15 premenopausal women to elucidate whether bone turnover is increased and bone mineral density is reduced due to endogenous subclinical hyperthyroidism. Each patient had normal free thyroxine (FT4) and free triiodothyronine (FT3) levels associated with a stable suppression (<0.1 mU/L) of serum thyrotropin (TSH) levels during a period ranging between 6 and 11 months. Metabolic parameters of bone turnover (serum osteocalcin, bone specific alkaline phosphatase, procollagen I C-terminal peptide reflecting bone formation; urinary deoxypyridinoline and calcium excretion reflecting bone resorption) were assessed. Bone mineral density was measured at lumbar 1-4 vertebrae, femoral neck, and the forearm (midshaft radius and distal radius) by dual energy x-ray absorptiometry. All measurements were compared with 15 healthy age-, height-, and weight-matched premenopausal women who served as control group. Our findings suggest that endogenous subclinical hyperthyroidism is not associated with increased bone turnover, and bone mineral density is not reduced in premenopausal women, at least in the short term.
Thyroid 1999 Jun
PMID:Effect of endogenous subclinical hyperthyroidism on bone metabolism and bone mineral density in premenopausal women. 1041 Nov 15

Thyroid hormone (T3) and insulin-like growth factor I (IGF-I) are critical regulators of skeletal function. T3 increases IGF-I production in bone. To assess the potential role of IGF-I as a mediator of T3 actions, we characterized phenotypic markers of osteoblast activity in two osteoblast models, normal mouse osteoblasts and MC3T3-E1 cells, exposed to T3 alone or under conditions that interfere with IGF-I actions. T3 significantly increased osteoblast 3H-proline incorporation, alkaline phosphatase (ALP), and osteocalcin. Both alphaIR3, a neutralizing monoclonal antibody to the IGF-I receptor, and JB1, an IGF-I analogue antagonist, attenuated the stimulatory effects of T3. T3 effects also were decreased in cells transfected with antisense oligonucleotide (AS-ODN) to the IGF-I receptor gene. Both IGF-I and T3 had mitogenic effects that were inhibited by the antagonists. IGF-I by itself did not stimulate 3H-proline incorporation, ALP, and osteocalcin in the models used, revealing that although IGF-I is essential for the anabolic effects of T3, it acts in concert with other factors to elicit these phenotypic responses.
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PMID:Insulin-like growth factor I production is essential for anabolic effects of thyroid hormone in osteoblasts. 1070 20

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally no significant association was seen between age-adjusted BMD and genotype, patients in remission for >5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (Z = 1.14 ff vs. Z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.
Thyroid 2000 May
PMID:Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease. 1088 83

For the treatment of differentiated thyroid cancer, surgery, radioiodide therapy, and thyrotropin-suppressive thyroxine application represent established therapeutic measures of proven efficiency, affording a good prognosis for this disease. However, in up to 30% of the cases, dedifferentiation is observed, giving rise to tumors that are refractory to conventional treatment. Eventually, this may lead to the most malignant human tumor, anaplastic thyroid carcinoma, with a life expectancy of only a few months after diagnosis. Among novel approaches for the treatment of dedifferentiated thyroid carcinomas, retinoic acid redifferentiation therapy was evaluated in several in vitro and in vivo studies. Cell culture experiments in thyroid carcinoma lines show that RA treatment affects thyroid specific functions (type I 5'-deiodinase, sodium/iodide-symporter), cell-cell or cell-matrix interaction (intercellular adhesion molecule-1, E-cadherin), differentiation markers (alkaline phosphatase, CD97), growth, and tumorigenicity. The observed changes, which involve multiple parameters that characterize a mature, functional thyrocyte, may be interpreted as partial redifferentiation. In clinical pilot studies, about 40% of the patients responded to RA application with an increased radioiodide uptake. In an evaluation of 20 RA-treated patients with well-documented data sets, 8 exhibited a decrease (4) or stabilization (4) in tumor size and/or in serum thyroglobulin levels in addition to enhanced radioiodide transport. This indicates that these patients with a long history of unresponsiveness to other treatment may have experienced an actual therapeutic benefit. These data suggest that RA redifferentiation therapy, considering especially its comparatively mild side effects, may soon represent an alternative therapeutic approach to otherwise untreatable thyroid tumors.
Thyroid 2000 May
PMID:Retinoic acid redifferentiation therapy for thyroid cancer. 1088 86

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally, no significant association was seen between age-adjusted BMD and genotype, patients in remission for fewer than 5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (z = 1.14 ff vs. z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.
Thyroid 2000 Jun
PMID:Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease. 1090 90

Thyroid hormone has been known for over 50 years to be a potent regulator of skeletal maturation at the growth plate. The receptor for thyroid hormone has been discovered to be a member of the nuclear hormone receptor superfamily. Retinoic acid and 1,25(OH)2 vitamin D3, whose receptors also belong to this nuclear hormone receptor family, have been implicated in the control of chondrocyte proliferation and differentiation at the growth plate. Recent studies demonstrate that the receptors for thyroid hormone, retinoic acid, and vitamin D bind to a similar DNA response element in the promoter region of target genes and may form heterodimers to regulate gene transcription in target cells. These observations led us to hypothesize that the retinoic acid and/or vitamin D signaling pathways may interact with thyroid hormone signaling at the molecular level to modulate growth plate chondrocyte differentiation. Using a chemically defined, serum-free model of growth plate chondrocyte maturation, both all-trans retinoic acid and 1,25(OH)2 vitamin D3 markedly inhibited thyroid hormone-induced terminal differentiation in a dose-dependent manner. In the absence of thyroid hormone, retinoic acid stimulated alkaline phosphatase activity modestly at the highest dose used, however neither retinoic acid nor 1,25(OH)2 vitamin D3 induced expression of type X collagen mRNA. We conclude that retinoic acid and vitamin D are likely to be antagonists of thyroid hormone signaling in the growth plate.
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PMID:Both retinoic acid and 1,25(OH)2 vitamin D3 inhibit thyroid hormone-induced terminal differentiaton of growth plate chondrocytes. 1133 19


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