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

---

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

In order to study osteoblast differentiation we subcloned a cell derived from a mouse a bone marrow stromal cell line, Kusa O, and obtained a number of clones representative of three different phenotypes. One that neither differentiated into osteoblasts nor into adipocytes, a second that differentiated into osteoblasts but not adipocytes, and a third that differentiated into both osteoblasts and adipocytes. Four subclones were selected for further characterization according to their ability to mineralize and/or differentiate into adipocytes. The non-mineralizing clone had no detectable alkaline phosphatase activity although some alkaline phosphatase mRNA was detected after 21 days in osteoblast differentiating medium. Alkaline phosphatase activity and mRNA in the three mineralizing clones were comparable with the parent clones. Osteocalcin mRNA and protein levels in the non-mineralizing clone were low and non-detectable, respectively, while both were elevated in the parent cells and mineralizing subclones after 21 days in differentiating medium. PTH receptor mRNA and activity increased in the four subclones and parent cells with differentiation. mRNA for two other osteoblast phenotypic markers, osteopontin and bone sialoprotein, were similarly expressed in the parent cells and subclones while mRNAs for the transcription factors, Runx2 and osterix, were detectable in both parent and subclone cells. Runx2 was unchanged with differentiation while osterix was increased. Interestingly, PPARgamma mRNA expression did not correlate with cell line potential to differentiate into adipocytes. Indian hedgehog mRNA and its receptor (patched) mRNA levels both increased with differentiation while mRNA levels of the Wnt pathway components beta-catenin and dickkopf also increased with differentiation. Although we have focussed on characterizing these clones from the osteoblast perspective it is clear that they may be useful for studying both osteoblast and adipocyte differentiation as well as their transdifferentiation.
...
PMID:Differentiation potential of a mouse bone marrow stromal cell line. 1293 65

We examined the effect of PTH-related peptide (PTHrP) on modulating adipogenesis and osteoblastogenesis in the pluripotent mesenchymal cell line C3H10T(1/2). These cells express the type 1 PTH/PTHrP receptor, thereby allowing PTHrP to inhibit bone morphogenetic protein 2 (BMP2) from enhancing gene expression of peroxisome proliferator-activated receptor gamma and the adipocyte-specific protein aP2 and from augmenting the accumulation of lipid. In the presence of BMP2, PTHrP or a protein kinase C (PKC) stimulator (phorbol ester) increased the expression of indexes of the osteoblast phenotype, including alkaline phosphatase, type I collagen, and osteocalcin, whereas a PKC inhibitor (chelerythrin chloride) inhibited PTHrP action. PTHrP and a phorbol ester increased gene expression of the BMP IA receptor, and both enhanced BMP2-dependent increases in promoter activity of the signaling molecule SMAD6. Overexpression of the BMP IA receptor facilitated the capacity of BMP2 to increase osteoblastogenesis in the absence of PTHrP and a dominant negative BMP IA receptor variant inhibited this effect of BMP2. These results demonstrate that PTHrP can direct osteoblastic, rather then adipogenic, commitment of mesenchymal cells, implicate PKC signaling in this activity, and show that PTHrP action involves enhanced gene expression of the BMP IA receptor, which facilitates BMP2 action in enhancing osteoblastogenesis in pluripotent mesenchymal cells.
...
PMID:Parathyroid hormone-related peptide interacts with bone morphogenetic protein 2 to increase osteoblastogenesis and decrease adipogenesis in pluripotent C3H10T 1/2 mesenchymal cells. 1296 89

In the present study, we investigated the role of the phytoestrogen genistein and 17beta-estradiol in human bone marrow stromal cells, undergoing induced osteogenic or adipogenic differentiation. Profiling of estrogen receptors (ERs)-alpha, -beta1, -beta2, -beta3, -beta4, -beta5, and aromatase mRNAs revealed lineage-dependent expression patterns. During osteogenic differentiation, the osteoblast-determining core binding factor-alpha1 showed a progressive increase, whereas the adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARgamma) was sequentially decreased. This temporal regulation of lineage-determining marker genes was strongly enhanced by genistein during the early osteogenic phase. Moreover, genistein increased alkaline phosphatase mRNA levels and activity, the osteoprotegerin:receptor activator of nuclear factor-kappaB ligand gene expression ratio, and the expression of TGFbeta1. During adipogenic differentiation, down-regulation in the mRNA levels of PPARgamma and CCAAT/enhancer-binding protein-alpha at d 3 and decreased lipoprotein lipase and adipsin mRNA levels at d 21 were observed after genistein treatment. This led to a lower number of adipocytes and a reduction in the size of their lipid droplets. At d 3 of adipogenesis, TGFbeta1 was strongly up-regulated by genistein in an ER-dependent manner. Blocking the TGFbeta1 pathway abolished the effects of genistein on PPARgamma protein levels and led to a reduction in the proliferation rate of precursor cells. Overall, genistein enhanced the commitment and differentiation of bone marrow stromal cells to the osteoblast lineage but did not influence the late osteogenic maturation markers. Adipogenic differentiation and maturation, on the other hand, were reduced by genistein (and 17beta-estradiol) via an ER-dependent mechanism involving autocrine or paracrine TGFbeta1 signaling.
...
PMID:The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. 1460 6

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-dependent transcription factor that regulates the expression of genes involved in lipid metabolism and transport. Ligands/activators of PPARalpha, like fibrate-type drugs, may have hypolipidemic effects. To identify food that contains activators of PPARalpha, a transactivation assay employing a clone of CHO-K1 cells stably transfected with a (UAS)(4)-tk-alkaline phosphatase reporter and a chimeric receptor of Gal4-rPPARalpha LBD was used to screen ethyl acetate (EA) extracts of a large variety of food materials. It was found that the EA extract of bitter gourd (Momordica charantia), a common oriental vegetable, activated PPARalpha to an extent that was equivalent to or even higher than 10 microM Wy-14643, a known ligand of PPARalpha. This extract also activated PPARgamma to a significant extent which was comparable to 0.5 microM BRL-49653. The activity toward PPARalpha was mainly in the soluble fraction of the organic solvent. The EA extract prepared from the whole fruit showed significantly higher activity than that from seeds or flesh alone. The bitter gourd EA extract was then incorporated into the medium for treatment of a peroxisome proliferator-responsive murine hepatoma cell line, H4IIEC3, for 72 h. Treated cells showed significantly higher activity of acyl CoA oxidase and higher expressions of mRNA of this enzyme and fatty acid-binding protein, indicating that the bitter gourd EA extract was able to act on a natural PPARalpha signaling pathway in this cell line. It is thus worth further investigating the PPAR-associated health benefits of bitter gourd.
...
PMID:Bitter gourd (Momordica charantia) extract activates peroxisome proliferator-activated receptors and upregulates the expression of the acyl CoA oxidase gene in H4IIEC3 hepatoma cells. 1463 Nov 18

Space flight-induced bone loss has been attributed to a decrease in osteoblast function, without a significant change in bone resorption. To determine the effect of microgravity (MG) on bone, we used the Rotary Cell Culture System [developed by the National Aeronautics and Space Administration (NASA)] to model MG. Cultured mouse calvariae demonstrated a 3-fold decrease in alkaline phosphatase (ALP) activity and failed to mineralize after 7 d of MG. ALP and osteocalcin gene expression were also decreased. To determine the effects of MG on osteoblastogenesis, we cultured human mesenchymal stem cells (hMSC) on plastic microcarriers, and osteogenic differentiation was induced immediately before the initiation of modeled MG. A marked suppression of hMSC differentiation into osteoblasts was observed because the cells failed to express ALP, collagen 1, and osteonectin. The expression of runt-related transcription factor 2 was also inhibited. Interestingly, we found that peroxisome proliferator-activated receptor gamma (PPARgamma2), which is known to be important for adipocyte differentiation, adipsin, leptin, and glucose transporter-4 are highly expressed in response to MG. These changes were not corrected after 35 d of readaptation to normal gravity. In addition, MG decreased ERK- and increased p38-phosphorylation. These pathways are known to regulate the activity of runt-related transcription factor 2 and PPARgamma2, respectively. Taken together, our findings indicate that modeled MG inhibits the osteoblastic differentiation of hMSC and induces the development of an adipocytic lineage phenotype. This work will increase understanding and aid in the prevention of bone loss, not only in MG but also potentially in age-and disuse-related osteoporosis.
...
PMID:Modeled microgravity inhibits osteogenic differentiation of human mesenchymal stem cells and increases adipogenesis. 1474 52

Mice deficient in the Msx2 gene manifest defects in skull ossification and a marked reduction in bone formation associated with decreases in osteoblast numbers, thus suggesting that Msx2 is involved in bone formation. However, the precise role of Msx2 during osteoblast differentiation is not fully understood. In the present study, we investigated the role of Msx2 in the regulation of osteoblast differentiation in the multipotent mesenchymal cell lines C3H10T1/2 and C2C12 and in murine primary osteoblasts. Introduction of Msx2 induced alkaline phosphatase activity in C3H10T1/2 and C2C12 cells and promoted the calcification of murine primary osteoblasts. This effect of Msx2 was also observed in mesenchymal cells isolated from Runx2-deficient mice. Interestingly the expression of Msx2 was induced by bone morphogenetic protein 2 treatment in Runx2-deficient mesenchymal cells. In contrast, Msx2 diminished peroxisome proliferator-activated receptor gamma (PPARgamma) expression and adipogenesis of the preadipocytic cell line 3T3-F442A. Moreover Msx2 inhibited the transcriptional activity of PPARgamma, CCAAT/enhancer-binding protein beta (C/EBPbeta), and C/EBPdelta and blocked adipocyte differentiation of mesenchymal cells induced by overexpression of PPARgamma, C/EBPalpha, C/EBPbeta, or C/EBPdelta. These data indicate that Msx2 promotes osteoblast differentiation independently of Runx2 and negatively regulates adipocyte differentiation through inhibition of PPARgamma and the C/EBP family.
...
PMID:Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. 1517 25

Mesenchymal stem cells capable of differentiating into multiple cell types are potentially useful therapeutically for regeneration of bone and cartilaginous tissues. Multipotent fibroblastic C3H10T1/2 cells are known to differentiate into osteoblasts, chondrocytes, and adipocytes in response to certain growth factors. In this study we compared the effects of bone morphogenetic protein (BMP)-2 on the differentiation of C3H10T1/2 and MC3T3-E1 preosteoblastic cells. Incubation of these cells with BMP-2 resulted in a dose- and time-dependent increase in alkaline phosphatase activity, but the increase in MC3T3-E1 cells was much higher than that in C3H10T1/2 cells. BMP-2 also induced differentiation of C3H10T1/2 cells but not MC3T3-E1 cells into chondrocytes and adipocytes. Reverse transcription-polymerase chain reaction analysis showed that these commitments were accompanied by the specific expression of osteocalcin, aggrecan, and PPARgamma. To investigate the in vivo differential property, these cells were inoculated with BMP-2 in a diffusion chamber and transplanted into the mouse peritoneal cavity for 4 weeks. The transplanted C3H10T1/2 cells formed mineralized bone containing chondrocytes and adipocytes, whereas MC3T3-E1 created only bony tissue. Our results indicate that BMP-2 can induce the differentiation of C3H10T1/2 into osteoblasts, chondrocytes, and adipocytes in both in vivo and in vitro conditions, and that C3H10T1/2 could be used to examine the BMP-2-induced regulatory mechanisms of mesenchymal differentiation.
...
PMID:Bone morphogenetic protein-2 induces differentiation of multipotent C3H10T1/2 cells into osteoblasts, chondrocytes, and adipocytes in vivo and in vitro. 1544 26

Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). In bone marrow stromal cell cultures and in vivo, activation of PPARgamma by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.
...
PMID:Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. 1552 88

Targeted gene studies have demonstrated the importance of insulin-like growth factor-I (IGF-I) for osteoblast (OB) differentiation and the acquisition of peak bone mineral density (BMD). The skeletal response to allelic differences in IGF-I expression can also be measured in vivo, using congenic mice. We created a congenic strain with reduced (approximately 20%) circulating IGF-I (C3H.B6-6T [6T]) by backcrossing a small genomic region (30 cM) of Chromosome 6 (Chr6) from C3H/HeJ (C3H) onto a C57Bl/6J (B6) background. 6T female mice have lower serum IGF-I (P<0.001 vs. B6) but similar growth hormone (GH) and serum IGF binding protein (IGFBP) concentrations as B6. At 16 weeks of age, congenics have greater body fat (P<0.02 vs. B6) despite less total body weight, and exhibit smaller femoral cross-sectional size (P=0.001), reduced cortical thickness (P<0.001) and lower trabecular BV/TV (P<0.05) than B6. 6T mice also have suppressed serum leptin (P<0.01), but compared to B6 have similar markers of bone resorption (i.e., urine CTx and serum TRAP 5B). At 8 weeks of age, skeletal IGF-I mRNA from long bones was reduced by 40% (P<0.05) as were liver mRNA transcripts (i.e., 50%, P<0.01). Osteoblast progenitors from the bone marrow of 6T mice formed less colony forming unit fibroblasts by crystal violet staining than B6 (P<0.007) and had significantly reduced alkaline phosphatase-positive colonies than B6(P<0.0001). In addition, staining of bone marrow with oil red O revealed greater numbers of adipocytes in 6T than B6. Several candidate genes in the Chr6 QTL were excluded by lack of strain-related expression differences in bone, but genes positively regulating adipocyte differentiation including Alox 5 and PPAR-gamma require further study as either "pathway" or candidate genes. In summary, allelic differences in a QTL on Chr6 result in altered IGF-I gene expression, changes in OB lineage allocation, and reduced peak bone mass. Congenic mice are useful models not only for mapping genes related to bone mass but also for elucidating the biology underlying various skeletal phenotypes associated with more subtle manipulation of the mouse genome.
...
PMID:Congenic mice with low serum IGF-I have increased body fat, reduced bone mineral density, and an altered osteoblast differentiation program. 1554 29

Osteoblasts and adipocytes originate from common mesenchymal progenitor cells. We have investigated whether mouse osteoblastic MC3T3-E1 cells can be induced to transdifferentiate into mature adipocytes by the ectopic expression of adipogenic transcription factors, PPARgamma, C/EBPalpha, or both. Retrovirus-mediated overexpression of PPARgamma alone or both PPARgamma and C/EBPalpha resulted in reduced alkaline phosphatase activity and osteoblast-specific gene expression. Moreover, foci of adipocytes were identified in conditions favoring osteoblastic maturation. Upon treatment with insulin, dexamethasone, and IBMX, cells overexpressing PPARgamma alone or both PPARgamma and C/EBPalpha showed marked transdifferentiation to mature adipocytes expressing molecular markers of adipocytes. Cells expressing both PPARgamma and C/EBPalpha showed more robust phenotype of adipocytes than the cells expressing PPARgamma alone. Overexpression of C/EBPalpha alone did not result in adipogenesis. These results suggest that PPARgamma is a key molecular switch for the transdifferentiation to adipocytes whereas C/EBPalpha may differentiate MC3T3-E1 cells into osteoblasts and adipocytes.
...
PMID:Ectopic overexpression of adipogenic transcription factors induces transdifferentiation of MC3T3-E1 osteoblasts. 1564 18


<< Previous 1 2 3 4 5 6 7 Next >>

---