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)

Parathyroid hormone (PTH-(1-34)) potently suppresses apatite deposition in osteoblastic cultures. These inhibitory effects are mediated through signaling events following PTH receptor binding. Using both selective inhibitors and activators of protein kinase A (PKA), this study shows that a transient activation of PKA is sufficient to account for PTH's inhibition of apatite deposition. This inhibition is not a result of reduced cell proliferation, reduced alkaline phosphatase activity, increased collagenase production, or lowering medium pH. Rather, data suggest a functional relationship between matrix assembly and apatite deposition in vitro. Bone sialoprotein (BSP) and apatite co-localize in the extracellular matrix of mineralizing cultures, with matrix deposition of BSP temporally preceding that of apatite. Transient activation of PKA by either PTH-(1-34) or short term cAMP analog treatment blocks the deposition of BSP in the extracellular matrix without a significant reduction in the total amount of BSP synthesized and secreted. This effect is reversible after allowing the cultures to recover in the absence of PKA activators for several days. Thus, a transient activation of PKA may suppress mineral deposition in vitro as a consequence of altering the assembly of an extracellular matrix permissive for apatite formation.
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PMID:Reversible suppression of in vitro biomineralization by activation of protein kinase A. 1075 13

The proliferation-differentiation behaviour of human alveolar bone cell cultures grown for 32 days in conditions that allowed the complete expression of the osteoblastic phenotype was significantly affected by the continuous presence of parathyroid hormone, 1, 25-dihydroxyvitamin D(3), or dexamethasone. Parathyroid hormone and, in particular, dexamethasone significantly induced the differentiation of osteoblastic cells. Moreover, cultures exposed to these hormones presented an earlier appearance and higher levels of alkaline phosphatase, and an increased ability to form calcium phosphate deposits in the extracellular matrix.
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PMID:Long-term effects of parathyroid hormone, 1,25-dihydroxyvitamin d(3), and dexamethasone on the cell growth and functional activity of human osteogenic alveolar bone cell cultures. 1098 95

Parathyroid hormone (1-34) (PTH(1-34) and transforming growth factor-beta1 (TGF-beta1) regulate chondrocyte proliferation, differentiation, and matrix synthesis. Both proteins mediate their effects in a dose- and time-dependent manner, and the effects are cell maturation specific. Moreover, similar signaling pathways are used, suggesting that there may be cross talk leading to coregulated cell response. To test this hypothesis, confluent cultures of rat costochondral resting zone and growth zone chondrocytes were treated with 0.22, 0.44, or 0.88 ng/mL of rhTGF-beta1 for 24 h, followed by treatment with 10(-11) to 10(-8) M PTH(1-34) for 10 min or 24 h. [3H]-Thymidine incorporation, specific activity of alkaline phosphatase (AP), and [35S]-sulfate incorporation were measured. PTH(1-34) had no effect on [3H]-thymidine incorporation by growth zone cells pretreated with 0.22 or 0.44 ng/mL of TGF-beta1, but in cultures treated with 0.88 ng/mL, PTH(1-34) caused a dose-dependent decrease that was maximal at the lowest concentration tested. By contrast, PTH(1-34) stimulated [3H]-thymidine incorporation by resting zone cells, and this effect was additive with the stimulation caused by 0.22 ng/mL of TGF-beta1. PTH(1-34) caused a synergistic increase in AP in growth zone cells treated with 0.44 or 0.88 ng/mL of TGF-beta1, but not in cells treated with 0.22 ng/mL of TGF-beta1. It had no effect on AP in resting zone cells pretreated with any concentration of TGF-beta1. PTH(1-34) increased [35S]-sulfate incorporation in growth zone and resting zone cell cultures treated with 0.22 ng/mL of TGF-beta1 to levels seen in cultures treated with 0.88 ng/mL of TGF-beta1 alone. These results support the hypothesis that PTH(1-34) and TGF-beta1 coregulate growth plate chondrocytes and that the effects are cell maturation dependent.
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PMID:Parathyroid hormone and transforming growth factor-beta1 coregulate chondrocyte differentiation in vitro. 1121 42

Despite improvements in medical management parathyroidectomy has an important role in treatment of refractory renal hyperparathyroidism (HPT). The medical records of all patients who underwent parathyroidectomy from 1991 through 2000 were reviewed to determine the clinical and laboratory features and outcomes of treatment in patients with renal versus primary HPT. Twenty-one of 92 patients who underwent parathyroidectomy had renal HPT with a mean age of 47+/-3 years compared with 56+/-2 years for patients with primary HPT (P < 0.05). Clinical manifestations included osteodystrophy (19), pruritus (six), extraosseous calcification (three), and calciphylaxis (one). Parathyroid hormone, phosphorus, and alkaline phosphatase levels and weights of excised glands were higher in renal versus primary HPT (P < 0.05). Supernumerary glands were found in three patients (14%) with renal HPT and none of nine patients with primary parathyroid hyperplasia. After surgical therapy persistent or recurrent HPT occurred in three (14%) patients with renal and one (1.4%) patient with primary HPT (P < 0.05). Postoperative hypocalcemia occurred in 20 (95%) patients with renal HPT all of whom required intravenous calcium, compared with 25 (35%) patients with primary HPT (P < 0.05) of whom only three (4%) required intravenous calcium (P < 0.05). In contrast to those with primary HPT patients with renal HPT are younger and more likely to have severe osteodystrophy, postoperative hypocalcemia, and persistent or recurrent HPT.
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PMID:Refractory renal hyperparathyroidism: clinical features and outcome of surgical therapy. 1130 95

Parathyroid hormone (PTH)-related peptide (PTHrP) can modulate the proliferation and differentiation of a number of cell types including osteoblasts. PTHrP can activate a G protein-coupled PTH/PTHrP receptor, which can interface with several second-messenger systems. In the current study, we have examined the signaling pathways involved in stimulated type I collagen and alkaline phosphatase expression in the human osteoblast-derived osteosarcoma cells, MG-63. By use of Northern blotting and histochemical analysis, maximum induction of these two markers of osteoblast differentiation occurred after 8 h of treatment with 100 nM PTHrP-(1-34). Chemical inhibitors of adenylate cyclase (H-89) or of protein kinase C (chelerythrine chloride) each diminished PTHrP-mediated type I collagen and alkaline phosphatase stimulation in a dose-dependent manner. These effects of PTHrP could also be blocked by inhibiting the Ras-mitogen-activated protein kinase (MAPK) pathway with a Ras farnesylation inhibitor, B1086, or with a MAPK inhibitor, PD-98059. Transient transfection of MG-63 cells with a mutant form of Galpha, which can sequester betagamma-subunits, showed significant downregulation of PTHrP-stimulated type I collagen expression, as did inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) by wortmannin. Consequently, the betagamma-PI 3-kinase pathway may be involved in PTHrP stimulation of Ras. Collectively, these results demonstrate that, acting via its G protein-coupled receptor, PTHrP can induce indexes of osteoblast differentiation by utilizing multiple, perhaps parallel, signaling pathways.
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PMID:Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. 1150 Mar 4

Parathyroid hormone increases due to hypocalcemia even in the early phases of renal insufficiency. At the same time, hyperphosphatemia develops due to decreasing renal excretion which, in turn, intensifies secondary hyperparathyroidism. The cornerstones for prevention and therapy of renal osteopathy are, therefore, efficient lowering of phosphate levels and the early substitution of vitamin-D3 metabolites. In a post marketing surveillance (PMS) of almost 2,000 dialysis patients with renal osteopathy, the course of therapy with Alfacalcidol (Bondiol) was observed over a 6-month period. In 55.9% of cases, Alfacalcidol was administered at a daily dose of 0.25 microg. In 26.6% of patients, Alfacalcidol was administered every second day at a dose of 0.25-1 microg/d. In 16.1% of patients, Alfacalcidol was administered as pulse-therapy, mostly at a dose of 1-2 microg once or twice per week. To lower phosphate levels, 54.8% of patients received calcium compounds, 9.2% aluminium compounds, and 21.7% aluminium compounds in combination with calcium compounds. 14.3% of patients did not receive phosphate binding agents. Two thirds of patients had received active vitamin-D3-metabolites prior to commencing therapy with alfacalcidol, most frequently calcitrol. In 58.1%, the dialysis solution used had a calcium concentration of 1.5 mmol/l (44.8%) or lower; whereas in 41.9%, a higher calcium concentration was used--mostly 1.75 mmol/l (3 8%). During the observation period, serum concentrations of calcium and phosphate remained constant, suggesting that the risk of hypercalcemia due to therapy with Alfacalcidol was not increased. It was found that elevated alkaline phosphatase and parathyroid hormone levels could be significantly lowered (statistically). These effects could be observed both in patients who had been previously treated with vitamin-D3-metabolites and in patients without prior therapy. Efficacy and tolerability of therapy with Alfacalcidol was assessed to be very high by the attending nephrologists.
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PMID:Alfacalcidol in the therapy of renal bone disease. 1177 Aug 36

Cystic fibrosis (CF) patients often have low bone mineral density (BMD) and may suffer from fractures and kyphosis. The pathogenesis of low BMD in CF is multifactorial. To study bone metabolism, we collected fasting serum and urine from 50 clinically stable CF adults (mean age 28 years) and 53 matched controls to measure markers of bone formation and bone resorption. The CF subjects had moderate lung disease (FEV1: 46.1 +/- 18.6% predicted) and malnutrition (BMI: 20.0 +/- 3.3 kg/m2). Only 3 subjects had normal BMD. CF subjects had higher urinary N-telopeptides of type I collagen (81.0 +/- 60.0 vs 49.0 +/- 24.2 nm BCE/mmol creatinine, p = 0.0006) and free deoxypyridinoline (7.3 +/- 5.0 vs 5.3 +/- 1.9 nM/mM, p = 0.004) levels than controls. Serum osteocalcin levels were similar in the two groups, a result confirmed by two immunoassays that recognize different epitopes on osteocalcin. Serum bone-specific alkaline phosphatase levels were elevated in CF patients (32.0 +/- 11.3 vs 21.8 +/- 7.0 U/l, p < 0.0001), but were much more closely associated with serum total alkaline phosphatase levels (r = 0.51, p = 0.001) than with age or gender. Parathyroid hormone levels were elevated (p = 0.007) and 25-hydroxyvitamin D levels were depressed (p = 0.0002) in the CF patients in comparison with controls. These results indicate that adults with CF have increased bone resorption with little change in bone formation. Medications that decrease bone resorption or improve calcium homeostasis may be effective therapies for CF bone disease.
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PMID:Abnormal bone turnover in cystic fibrosis adults. 1190 25

The mRNA level of basic helix-loop-helix transcription factor DEC1 (BHLHB2)/Stra13/Sharp2 was up-regulated during chondrocyte differentiation in cultures of ATDC5 cells and growth plate chondrocytes, and in growth plate cartilage in vivo. Forced expression of DEC1 in ATDC5 cells induced chondrogenic differentiation, and insulin increased this effect of DEC1 overexpression. Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) suppressed DEC1 expression and the differentiation of ATDC5 cells, but DEC1 overexpression antagonized this inhibitory action of PTH/PTHrP. Transforming growth factor-beta or bone morphogenetic protein-2, as well as insulin, induced DEC1 expression in ATDC5 cultures where it induced chondrogenic differentiation. In pellet cultures of bone marrow mesenchymal stem cells exposed to transforming growth factor-beta and insulin, DEC1 was induced at the earliest stage of chondrocyte differentiation and also at the hypertrophic stage. Overexpression of DEC1 in the mesenchymal cells induced the mRNA expressions of type II collagen, Indian hedgehog, and Runx2, as well as cartilage matrix accumulation; overexpression of DEC1 in growth plate chondrocytes at the prehypertrophic stage increased the mRNA levels of Indian hedgehog, Runx2, and type X collagen, and also increased alkaline phosphatase activity and mineralization. To our knowledge, DEC1 is the first transcription factor that can promote both chondrogenic differentiation and terminal differentiation.
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PMID:Basic helix-loop-helix protein DEC1 promotes chondrocyte differentiation at the early and terminal stages. 1238 5

Juvenile idiopathic osteoporosis (JIO) is rare, presenting with vertebral fractures in the immediate prepubertal years; however, recovery is normally observed. We report the case of a 19-year-old pregnant woman previously diagnosed with JIO. She experienced three vertebral fractures in the third trimester of pregnancy. She delivered by caesarean section at 38 weeks gestation. Spinal bone mineral density decreased by 25%, hip bone mineral density by 10%, and forearm bone mineral density by 3% during pregnancy. Bone resorption markers, free pyridinoline and deoxypyridinoline (fPYD and fDPD), were elevated at baseline and markedly increased during pregnancy (fPYD/fDPD at 0, 10, 15, 20, and 28 weeks and immediately postpartum: 36.2/11.5, 52.9/15.8, 54.3/13.3, 51.1/13.3, 90/21.8, and 95.6/22.7 nmol/mmol creatinine, respectively) The bone formation marker, bone-specific alkaline phosphatase (BSAP), was within the reference range at baseline and increased in the third trimester. (BSAP at 0, 10, 15, 20, and 28 weeks and immediately postpartum: 20.5, 18.3, 17.7, 19.8, 26.9, and 30.0 U/liter, respectively). Parathyroid hormone (PTH) was measured by two methods to assess the possible effect of PTH fragments. PTH(1-84) (Roche) showed little change during the pregnancy, whereas the Nichols assay [(1-84) and(7-84) PTH fragment], revealed increases paralleling the changes in bone resorption. This young woman's bone turnover showed an exaggerated response to pregnancy, with bone resorption predominating over formation. PTH fragments may have partially mediated this effect.
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PMID:Effect of pregnancy on bone mineral density and biochemical markers of bone turnover in a patient with juvenile idiopathic osteoporosis. 1251 Aug 20

Parathyroid hormone (PTH) has biphasic effects on bone: continuous treatment is catabolic whereas intermittent treatment is anabolic. The mechanism(s) responsible for these differing effects are still unclear, partly because of the previous non-availability of a model system in which effects on both formation and resorption indices could be studied concomitantly. In cultured marrow cells from 6-week old C57BL/6 mice, we demonstrated that 4 days of intermittent PTH treatment increased mRNA for osteoblast differentiation markers (Runx2, alkaline phosphatase (AP), and type I procollagen (COL1A1) whereas continuous treatment resulted in production of large numbers of TRAP-positive multinucleated osteoclasts. Although IGF-I mRNA did not increase after intermittent treatment, it was consistently higher than after continuous treatment, and the addition of an anti-IGF-I neutralizing antibody prevented the increase in bone formation indices observed with intermittent treatment. By contrast, after continuous treatment, gene expression of RANK ligand (RANKL) was increased and that of osteoprotegerin (OPG) was decreased, resulting in a 25-fold increase in the RANKL/OPG ratio. In this model system, the data suggest that intermittent PTH treatment enhances osteoblast differentiation through an IGF-I dependent mechanism and continuous PTH treatment enhances osteoclastogenesis through reciprocal increases in RANKL and decreases in OPG.
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PMID:Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone. 1268 18


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