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)

The increasing interest in strontium incorporation into biomaterials for hard tissue repair is justified by the growing evidence of its beneficial effect on bone. We successfully synthesized hydroxyapatite (HA) thin films with different extents of strontium substitution for calcium (0, 1, 3 or 7 at.%) by pulsed-laser deposition. The coatings displayed a granular surface and a good degree of crystallinity, which slightly diminished as strontium content increased. Osteoblast-like MG63 cells and human osteoclasts were cultured on the thin films up to 21 days. MG63 cells grown on the strontium-doped HA coatings displayed normal morphology, good proliferation and increased values of the differentiation parameters, whereas the number of osteoclasts was negatively influenced by the presence of strontium. The positive effect of the ion on bone cells was particularly evident in the case of coatings deposited from HA at relatively high strontium contents (3-7%), where significantly increased values of alkaline phosphatase activity, osteocalcin, type I collagen and osteoprotegerin/TNF-related activation-induced cytokine receptor ratio, and considerably reduced values of osteoclast proliferation, were observed.
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PMID:Strontium-substituted hydroxyapatite coatings synthesized by pulsed-laser deposition: in vitro osteoblast and osteoclast response. 1855 96

Recent studies have indicated a link between bone metabolism and cardiovascular events in patients with chronic kidney disease (CKD). CKD is a major health problem worldwide. This study evaluates the role of noninvasive markers of bone metabolism in predicting cardiovascular morbidity (coronary artery disease, peripheral vascular disease, stroke) and mortality in patients with mild to severe forms of CKD. In a prospective cohort study, 627 patients with CKD were screened. To focus on bone metabolism, traditional risk factors for cardiovascular events were excluded, and 135 patients with CKD stages 1-5 were followed for 4 yr. Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. PTH (measured by four different assays), vitamin D 25 and 1,25, bone-specific alkaline phosphatase (BSALP), TRACP-5b, osteocalcin, serum collagen cross-link molecules, RANKL, and osteoprotegerin were determined. Predictors of cardiovascular events were evaluated by multivariable logistic regression, Kaplan-Meier survival, and Cox regression analysis. There were a total of 45 cardiovascular events (33%). Event rates were 5.6%, 29.1%, 45.2%, and 45.0% in CKD stages 1-2, 3, 4, and 5, respectively. In logistic regression, cardiovascular events were predicted only by (1) CKD stage (independent of age or sex; p < 0.001); (2) BSALP (p = 0.03); and (3) TRACP-5b (p = 0.04). Markers of bone formation (BSALP) and resorption (TRACP-5b) can serve as predictors of cardiovascular morbidity and mortality in CKD.
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PMID:Bone markers predict cardiovascular events in chronic kidney disease. 1859 36

Age-related osteoporosis is characterized by low bone mass, poor bone quality, and impaired osteoblastogenesis. Recently, the Hutchinson-Gilford progeria syndrome (HGPS), a disease of accelerated aging and premature osteoporosis, has been linked to mutations in the gene encoding for the nuclear lamina protein lamin A/C. Here, we tested the hypothesis that inhibition of lamin A/C in osteoblastic lineage cells impairs osteoblastogenesis and accelerates osteoclastogenesis. Lamin A/C was knocked-down with small interfering (si)RNA molecules in human bone marrow stromal cells (BMSCs) differentiating toward osteoblasts. Lamin A/C knockdown led to an inhibition of osteoblast proliferation by 26% and impaired osteoblast differentiation by 48% based on the formation of mineralized matrix. In mature osteoblasts, expression levels of runx2 and osteocalcin mRNA were decreased by lamin A/C knockdown by 44% and 78%, respectively. Furthermore, protein analysis showed that osteoblasts with diminished levels of lamin A/C also secreted less osteocalcin and expressed a lower alkaline phosphatase activity (-50%). Lamin A/C inhibition increased RANKL mRNA and protein levels, whereas osteoprotegerin (OPG) expression was decreased, resulting in an increased RANKL/OPG ratio and an enhanced ability to support osteoclastogenesis, as reflected by a 34% increase of TRACP(+) multinucleated cells. Our data indicate that lamin A/C is essential for proper osteoblastogenesis. Moreover, lack of lamin A/C favors an osteoclastogenic milieu and contributes to enhanced osteoclastogenesis.
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PMID:Inhibition of lamin A/C attenuates osteoblast differentiation and enhances RANKL-dependent osteoclastogenesis. 1876 23

The OPG/RANKL system in primary cultures of human osteoblasts has been studied by different authors. However, very few studies have been performed on gene expression of RANKL and OPG at different stages of maturation on human osteoblast cultures. The effect of 17- beta-estradiol and 1,25dihydroxyvitamin D3 on the OPG/RANKL system is not known during the different states of cellular maturation. In this work we quantified OPG and RANKL protein levels (ELISA) and the mRNA of OPG, RANKL, collagen type I, alkaline phosphatase, and osteocalcin (semi-quantitative RT-PCR) in human osteoblasts. We analyzed these in basal conditions and after incubation with 17- beta-estradiol and 1,25dihydroxyvitamin D3 in the first and second phases. We found that OPG secretion and expression levels increased throughout cellular growth. RANKL proteins were detected only in the first stage, and the expression increased throughout the first phase. Thus, the RANKL/OPG ratio was higher in immature osteoblasts than in mature osteoblasts. The evolution of RANKL gene expression was related to collagen I and alkaline phosphatase, while OPG was related to osteocalcin. We observed no modifications after estradiol and 1,25dihydroxyvitamin D3 treatment. Our results suggest that the OB is a positive stimulator at precocious stages of differentiation on osteoclastogenic modulates.
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PMID:Modifying RANKL/OPG mRNA expression in differentiating and growing human primary osteoblasts. 1893 23

Although the effects of coumestrol on osteoblasts and osteoclasts can be summarized as increasing the bone density and preventing bone resorption, direct and detailed effects of coumestrol on bone marrow stromal cells remain obscure. In the present study, the effects of coumestrol on proliferation and osteoblastic differentiation of rat bone marrow stromal cells (BMSCs) have been investigated; the regulative effect of coumestrol on BMSCs and skeletal system has also been discussed. The results showed that treatment with coumestrol increased cellular activities (analyzed by MTT assay), alkaline phosphatase (ALP), type I collagen and osteocalcin (OCN) activity as well as the protein and gene expression of OPG, gene expression ratio of OPG/RANKL and gene expression of estrogen receptor alpha(ERalpha). These results demonstrate that phytoestrogen coumestrol has a direct enhancing effect on the proliferation and osteogenic differentiation of bone marrow stromal cells, which would lead to stimulation of bone formation, and it can also protect the whole skeletal system by regulating OPG/RANKL expression, and these effects may be mediated by ERalpha.
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PMID:Coumestrol promotes proliferation and osteoblastic differentiation in rat bone marrow stromal cells. 1916 72

Multiple myeloma (MM) is a plasma cell malignancy characterized by a high capacity to induce osteolytic bone lesions. MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation, which plays a critical role in the bone-destructive process. Although the mechanism of estrogen action on bone cells and myeloma cells has been widely investigated, estrogen action on bone cells in MM is unknown. In this study, the effects of the gonadal hormone 17beta-estradiol on cell growth, alkaline phosphatase (ALP) activity, mineralization capacity, and RANKL/OPG ratios in primary rat osteoblasts cultured with MM cell conditioned medium (CM) or co-cultured with RPMI8226 cells were investigated. Treatments of 10(-2) to 10 nM 17beta-estradiol reversed inhibition of proliferation and ALP activity of osteoblasts by myeloma cells in a dose-dependent manner, and 10(-2) to 1 nM 17beta-estradiol reversed inhibition of the mineralization capacity of osteoblasts by myeloma cells. In co-culture experiments with primary rat osteoblasts and myeloma cells, treatments of 10(-2) to 10 nM 17beta-estradiol down-regulated transcription and secretion of RANKL and up-regulated transcription and secretion of OPG in the osteoblasts, reversing the effects of co-cultured myeloma cells. These findings suggest that 17beta-estradiol may temper the inhibitory effects of myeloma cells on osteoblasts and improve RANKL/OPG balance, providing a new agent for treatment of bone disease in myeloma.
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PMID:17beta-Estradiol overcomes human myeloma RPMI8226 cell suppression of growth, ALP activity, and mineralization in rat osteoblasts and improves RANKL/OPG balance in vitro. 1916 63

It has been suggested that hormones released after nutrient absorption, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 2 (GLP-2), could be responsible for changes in bone resorption. However, information about the role of GLP-1 in this regard is scanty. Diabetes-related bone loss occurs as a consequence of poor control of glucose homeostasis, but the relationship between osteoporosis and type 2 diabetes remains unclear. Since GLP-1 is decreased in the latter condition, we evaluated some bone characteristics in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rat models compared to normal (N) and the effect of GLP-1 or saline (control) treatment (3 days by osmotic pump). Blood was taken before and after treatment for plasma measurements; tibiae and femora were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis. Compared to N, plasma glucose and insulin were, respectively, higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b were lower; phosphate in IR showed a tendency to be higher; PTH was not different in T2D and IR; all parameters were unchanged after GLP-1 infusion. Bone OC, osteoprotegerin (OPG) and RANKL mRNA were lower in T2D and IR; GLP-1 increased OC and OPG in all groups and RANKL in T2D. Compared to N, trabecular bone parameters showed an increased degree of anisotropy in T2D and IR, which was reduced after GLP-1. These findings show an insulin-independent anabolic effect of GLP-1 and suggest that GLP-1 could be a useful therapeutic agent for improving the deficient bone formation and bone structure associated with glucose intolerance.
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PMID:Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states. 1921 81

Selection of cells having the most osteogenic potential is a strategy used in bone tissue engineering. Preclinical studies using murine bone marrow cells must consider the large amount of hematopoietic cells in the adherent fraction. The aim of this study was to enrich a murine bone marrow cell population with osteoprogenitors by using a simple and reliable method. Bone marrow from C57Bl/6 mice was extracted and cells which adhered onto plastic were expanded in primary culture for 14 days. Immunolabeling of the CD11b surface antigen was performed and the CD11b(-) cell fraction was isolated by FACS. Sorted and unsorted populations were analyzed for gene expression of osteoblast differentiation, alkaline phosphatase (AlkP) activity and matrix mineralization capacities. Selection of CD11b(-) cells increased the number of AlkP(+) cells from the plastic adherent fraction from 6.3% +/- 0.8 to 56% +/- 3.3 with a sevenfold increase in AlkP activity. mRNA analysis revealed a significant increase in the CD11b(-) fraction for Osterix (41-fold), RANKL (17-fold), M-CSF (8-fold) and Runx-2 (8-fold). An osteogenic population was obtained with improved capacities to produce a mineralized extracellular matrix in vitro, independently of the presence of glucocorticoids in the culture medium.
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PMID:Isolation of osteoprogenitors from murine bone marrow by selection of CD11b negative cells. 1922 88

Binge alcohol-related bone damage is prevented by concurrent administration of bisphosphonates, suggesting an activation of bone resorption with patterned alcohol exposure. Although chronic alcohol abuse is known to cause osteopenia, little is known about the effects of binge drinking on bone metabolism. We examined the effects of binge alcohol exposure on the relationship between bone damage and modulation of bone remodeling-specific gene expression profiles. Our hypothesis was that bone damage observed in young adult rats after binge alcohol exposure is associated with differential expression of bone remodeling-related gene expression. We further hypothesized that this differential gene expression specific to bone remodeling (bone resorption or formation related) would be influenced by the duration of binge alcohol exposure. Binge alcohol (3 g/kg, i.p.) was administered on 3 consecutive days each week, for 1 or 4 weeks, to adult male rats. Matched control animals were injected with an equal volume of isotonic saline. Lumbar vertebrae, L4-5, were analyzed for the presence of bone damage by quantitative computed tomography and compressive strength analysis. Total RNA was isolated from an adjacent vertebrae (L3), and whole transcriptome gene expression data were obtained for each sample. The expression levels of a subset of bone formation and resorption-associated differentially expressed genes were validated by quantitative reverse transcriptase-polymerase chain reaction. Bone loss was not observed after 1 week of treatment but was observed after four binge alcohol cycles with a 23% decrease in cancellous bone mineral density and 17% decrease in vertebral compressive strength compared with control values (P < 0.05). We observed that the duration of binge alcohol treatment influenced the modulation of expression profiles for genes that regulate the bone formation process. The expression of key bone formation-related marker genes such as osteocalcin and alkaline phosphatase were significantly reduced (P < 0.05) after acute binge alcohol exposure, and expression of regulators of osteoblast activity such as bone morphogenetic proteins and parathyroid hormone receptor displayed significantly (P < 0.05) decreased differential expression. The expression of sclerostin, a key canonical Wnt inhibitory protein, was significantly increased after acute binge alcohol treatment. The expression of important regulators of osteoclast maturation and activity such as NF-kappabeta (nuclear factor kappabeta) ligand (RANKL) and interleukin-6 were significantly increased (P < 0.05) by binge alcohol, and osteoprotegerin levels were significantly decreased (P < 0.05) in vertebral bone. These results show that expression patterns of several key bone remodeling genes are significantly perturbed by binge alcohol treatment, suggesting that perturbation of gene expression associated with bone remodeling may be one mechanism contributing to the disruption of bone mass homeostasis and subsequent bone loss observed after binge alcohol exposure in rodents.
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PMID:Binge alcohol-induced bone damage is accompanied by differential expression of bone remodeling-related genes in rat vertebral bone. 1933 Feb 77

The vitamin D endocrine system is essential for calcium and phosphate homeostasis and skeletal mineralization. The 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) hormone binds to the vitamin D receptor (VDR) to regulate gene expression. These gene products in turn mediate the actions of 1,25(OH)(2)D(3) in mineral-regulating target cells such as the osteoblast. We showed previously that meningioma 1 (MN1) is a novel target of 1,25(OH)(2)D(3) in MG-63 osteoblastic cells and that it is a coactivator for VDR-mediated transcription (Sutton, A. L., Zhang, X., Ellison, T. I., and MacDonald, P. N. (2005) Mol. Endocrinol. 19, 2234-2244). However, the functional significance of MN1 in osteoblastic cell biology is largely unknown. Here, we demonstrate that MN1 expression is increased dramatically during differentiation of primary osteoblastic cells. Using calvarial osteoblasts derived from wild-type and MN1 knock-out mice, we provide data supporting an essential role of MN1 in maintaining appropriate osteoblast proliferation, differentiation, and function. MN1 knock-out osteoblasts displayed altered morphology, decreased growth rate, impaired motility, and attenuated 1,25(OH)(2)D(3)/VDR-mediated transcription as well as reduced alkaline phosphatase activity and mineralized nodule formation. MN1 null osteoblasts were also impaired in supporting osteoclastogenesis in co-culture studies presumably because of marked reduction in the RANKL:OPG ratio in the MN1 null cells. Mechanistic studies supported a transcriptional role for MN1 in controlling RANKL gene expression through activation of the RANKL promoter. Cumulatively, these studies indicate an important role for MN1 in maintaining the appropriate maturation and function of calvarial osteoblasts.
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PMID:Meningioma 1 is required for appropriate osteoblast proliferation, motility, differentiation, and function. 1938 90


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