Source:http://linkedlifedata.com/resource/pubmed/id/11451955
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
39
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| pubmed:dateCreated |
2001-9-24
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| pubmed:abstractText |
Transforming growth factor-beta (TGF-beta) regulates osteoclastogenesis and osteoclast survival, in part through the induction of osteoprotegerin (OPG), a protein known to inhibit osteoclast formation and function. To explore the molecular basis of TGF-beta regulation of OPG expression, we evaluated the effects of TGF-beta on osteoclast formation, OPG protein secretion, mRNA expression, and gene transcription. The marked inhibitory effect of TGF-beta on osteoclast differentiation was confirmed in a co-culture model utilizing murine stromal/osteoblastic BALC cells and bone marrow hematopoietic precursors. This inhibition in osteoclast differentiation was preceded by a decrease in RANKL mRNA expression (5-fold) and a reciprocal increase in OPG mRNA (6.1-fold) and protein (7.1-fold) expression in BALC cells. At the promoter/transcriptional level, TGF-beta treatment resulted in a 3-10-fold increase in reporter gene activity directed by a 5.9-kilobase fragment of the human OPG promoter in transfection assays performed in UMR106 cells. The effect of TGF-beta was mimicked by TGF-beta2 and -beta3 but not by BMP-4, suggesting a TGF-beta signal-specific effect. Deletion analysis revealed that a 183-base pair region (-372 to -190) in the promoter was required for TGF-beta responsiveness, and this region was sufficient to confer TGF-beta inducibility to a heterologous (osteocalcin) minimal promoter. Substitution mutations that disrupted the Cbfa1- and/or Smad-binding elements present in the 183-base pair region resulted in a decrease in base-line expression and in the responsiveness to TGF-beta and Cbfa1. Collectively, these studies indicate the involvement and possible interaction of Cbfa1 and Smad proteins in mediating the effects of TGF-beta on OPG transcription.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Osteoprotegerin,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Isoforms,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Tumor Necrosis Factor,
http://linkedlifedata.com/resource/pubmed/chemical/TNFRSF11B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Tnfrsf11b protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta,
http://linkedlifedata.com/resource/pubmed/chemical/beta-Galactosidase
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| pubmed:status |
MEDLINE
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| pubmed:month |
Sep
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| pubmed:issn |
0021-9258
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
28
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| pubmed:volume |
276
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
36241-50
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| pubmed:dateRevised |
2008-11-21
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| pubmed:meshHeading |
pubmed-meshheading:11451955-Animals,
pubmed-meshheading:11451955-Bone Marrow Cells,
pubmed-meshheading:11451955-Cell Differentiation,
pubmed-meshheading:11451955-Cell Line,
pubmed-meshheading:11451955-Cells, Cultured,
pubmed-meshheading:11451955-Cloning, Molecular,
pubmed-meshheading:11451955-Coculture Techniques,
pubmed-meshheading:11451955-Dose-Response Relationship, Drug,
pubmed-meshheading:11451955-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:11451955-Glycoproteins,
pubmed-meshheading:11451955-Humans,
pubmed-meshheading:11451955-Mice,
pubmed-meshheading:11451955-Mutation,
pubmed-meshheading:11451955-Osteoclasts,
pubmed-meshheading:11451955-Osteoprotegerin,
pubmed-meshheading:11451955-Promoter Regions, Genetic,
pubmed-meshheading:11451955-Protein Binding,
pubmed-meshheading:11451955-Protein Isoforms,
pubmed-meshheading:11451955-RNA, Messenger,
pubmed-meshheading:11451955-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:11451955-Receptors, Tumor Necrosis Factor,
pubmed-meshheading:11451955-Signal Transduction,
pubmed-meshheading:11451955-Time Factors,
pubmed-meshheading:11451955-Transcription, Genetic,
pubmed-meshheading:11451955-Transfection,
pubmed-meshheading:11451955-Transforming Growth Factor beta,
pubmed-meshheading:11451955-beta-Galactosidase
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| pubmed:year |
2001
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| pubmed:articleTitle |
Stimulation of osteoprotegerin (OPG) gene expression by transforming growth factor-beta (TGF-beta). Mapping of the OPG promoter region that mediates TGF-beta effects.
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| pubmed:affiliation |
Gene Regulation, Bone and Inflammation Research, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285, USA.
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| pubmed:publicationType |
Journal Article
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