The University of Southampton
University of Southampton Institutional Repository

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.

Text
Accepted Manuscript-Greenhough J et al.pdf - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (1MB)
Text
Supplementary Information for Accepted Manuscript-Greenhough J et al.pdf - Other
Available under License Creative Commons Attribution.
Download (886kB)

More information

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

Catalogue record

Date deposited: 09 Sep 2016 10:58
Last modified: 18 Feb 2021 17:02

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×