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Regulation of osteoblast development by Bcl-2-associated athanogene-1 (BAG-1)

Regulation of osteoblast development by Bcl-2-associated athanogene-1 (BAG-1)
Regulation of osteoblast development by Bcl-2-associated athanogene-1 (BAG-1)
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-beta-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.
1-15
Greenhough, Joanna
60418140-9d6d-485b-a1bf-1b9a038560b4
Papadakis, Manos
ac2d55b0-7788-4157-a6c6-d8c87bcfdbe0
Cutress, Ramsey
68ae4f86-e8cf-411f-a335-cdba51797406
Townsend, Paul
54e7bb11-feba-4886-b792-ab0f93c9c734
Oreffo, Richard
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Tare, Rahul
587c9db4-e409-4e7c-a02a-677547ab724a
Greenhough, Joanna
60418140-9d6d-485b-a1bf-1b9a038560b4
Papadakis, Manos
ac2d55b0-7788-4157-a6c6-d8c87bcfdbe0
Cutress, Ramsey
68ae4f86-e8cf-411f-a335-cdba51797406
Townsend, Paul
54e7bb11-feba-4886-b792-ab0f93c9c734
Oreffo, Richard
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Tare, Rahul
587c9db4-e409-4e7c-a02a-677547ab724a

Greenhough, Joanna, Papadakis, Manos, Cutress, Ramsey, Townsend, Paul, Oreffo, Richard and Tare, Rahul (2016) Regulation of osteoblast development by Bcl-2-associated athanogene-1 (BAG-1). Scientific Reports, 6, 1-15, [33504]. (doi:10.1038/srep33504).

Record type: Article

Abstract

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-beta-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.

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Accepted/In Press date: 25 August 2016
e-pub ahead of print date: 16 September 2016
Organisations: Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, Human Development & Health

Identifiers

Local EPrints ID: 400090
URI: http://eprints.soton.ac.uk/id/eprint/400090
PURE UUID: 20558566-e2d2-4a85-a2da-7e9f942718e6
ORCID for Richard Oreffo: ORCID iD orcid.org/0000-0001-5995-6726
ORCID for Rahul Tare: ORCID iD orcid.org/0000-0001-8274-8837

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Date deposited: 09 Sep 2016 10:58
Last modified: 15 Mar 2024 05:52

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Contributors

Author: Joanna Greenhough
Author: Manos Papadakis
Author: Ramsey Cutress
Author: Paul Townsend
Author: Richard Oreffo ORCID iD
Author: Rahul Tare ORCID iD

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