Regulation of osteoblast development by Bcl-2-associated athanogene-1 (BAG-1)
| Autor: | Greenhough, Joanna, Papadakis, Emmanouil S., Cutress, Ramsey I., Townsend, Paul A., Oreffo, Richard O. C., Tare, Rahul S. |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Thiazoles/metabolism
Heterozygote Cell Survival Bone Morphogenetic Protein 2 Bone Marrow Cells/cytology Gene Expression Regulation/drug effects Apoptosis Bone Marrow Cells Haploinsufficiency Haploinsufficiency/drug effects Article Cell Proliferation/drug effects HSC70 Heat-Shock Proteins/metabolism Mice Osteogenesis Animals DNA/metabolism Benzothiazoles Cells Cultured Cell Proliferation Bone Morphogenetic Protein 2/pharmacology Peptides/pharmacology Osteoblasts Estrogens/pharmacology Manchester Cancer Research Centre ResearchInstitutes_Networks_Beacons/mcrc Apoptosis/drug effects HSC70 Heat-Shock Proteins Osteoblasts/cytology Cell Differentiation Estrogens DNA Transcription Factors/chemistry Osteogenesis/drug effects DNA-Binding Proteins Thiazoles Gene Expression Regulation Receptors Estrogen Cell Differentiation/drug effects Female Receptors Estrogen/metabolism Peptides Transcription Factors Cell Survival/drug effects DNA-Binding Proteins/chemistry |
| Zdroj: | Greenhough, J, Papadakis, E S, Cutress, R I, Townsend, P A, Oreffo, R O C & Tare, R S 2016, ' Regulation of osteoblast development by Bcl-2-associated athanogene-1 (BAG-1) ', Scientific Reports, vol. 6, pp. 33504 . https://doi.org/10.1038/srep33504 Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep33504 |
| Popis: | BCL-2-associated athanogene-1 (BAG-1) is expressed by osteoblast-lineage cells; early embryonic lethality in Bag-1 null mice, however, has limited the investigation of BAG-1 function in osteoblast development. In the present study, bone morphogenetic protein-2/BMP-2-directed osteogenic differentiation of bone marrow stromal cells (BMSCs) of Bag-1(+/-) (heterozygous) female mice was decreased significantly. Genes crucial for osteogenic differentiation, bone matrix formation and mineralisation were expressed at significantly lower levels in cultures of Bag-1(+/-) BMSCs supplemented with BMP-2, while genes with roles in inhibition of BMP-2-directed osteoblastogenesis were significantly upregulated. 17-β-estradiol (E2) enhanced responsiveness of BMSCs of wild-type and Bag-1(+/-) mice to BMP-2, and promoted robust BMP-2-stimulated osteogenic differentiation of BMSCs. BAG-1 can modulate cellular responses to E2 by regulating the establishment of functional estrogen receptors (ERs), crucially, via its interaction with heat shock proteins (HSC70/HSP70). Inhibition of BAG-1 binding to HSC70 by the small-molecule chemical inhibitor, Thioflavin-S, and a short peptide derived from the C-terminal BAG domain, which mediates binding with the ATPase domain of HSC70, resulted in significant downregulation of E2/ER-facilitated BMP-2-directed osteogenic differentiation of BMSCs. These studies demonstrate for the first time the significance of BAG-1-mediated protein-protein interactions, specifically, BAG-1-regulated activation of ER by HSC70, in modulation of E2-facilitated BMP-2-directed osteoblast development. |
| Databáze: | OpenAIRE |
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