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dc.contributor.authorStegen, Steve
dc.contributor.authorStockmans, Ingrid
dc.contributor.authorMoermans, Karen
dc.contributor.authorTheinpont, Bernard
dc.contributor.authorMaxwell, Patrick H
dc.contributor.authorCarmeliet, Peter
dc.contributor.authorCarmeliet, Geert
dc.date.accessioned2018-10-04T08:38:54Z
dc.date.available2018-10-04T08:38:54Z
dc.date.issued2018-07-02
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283183
dc.description.abstractPreservation of bone mass is crucial for healthy ageing and largely depends on adequate responses of matrix-embedded osteocytes. These cells control bone formation and resorption concurrently by secreting the WNT/-catenin antagonist sclerostin (SOST). Osteocytes reside within a low oxygen microenvironment, but whether and how oxygen sensing regulates their function remains elusive. Here, we show that conditional deletion of the oxygen sensor prolyl hydroxylase (PHD) 2 in osteocytes results in a high bone mass phenotype, which is caused by increased bone formation and decreased resorption. Mechanistically, enhanced HIF-1 signalling increases Sirtuin 1-dependent deacetylation of the Sost promoter, resulting in decreased sclerostin expression and enhanced WNT/-catenin signalling. Additionally, genetic ablation of PHD2 in osteocytes blunts osteoporotic bone loss induced by estrogen deficiency or mechanical unloading. Thus, oxygen sensing by PHD2 in osteocytes negatively regulates bone mass through epigenetic regulation of sclerostin and targeting PHD2 elicits an osteo-anabolic response in osteoporotic models.
dc.description.sponsorshipResearch Foundation – Flanders (FWO: G.0A72.13, G.096414 and G0A4216N) and P.C. from long-term structural funding – Methusalem Funding by the Flemish Government.
dc.languageeng
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleOsteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin
dc.typeArticle
prism.number2557
prism.publicationNameNature Communications
prism.volume9
dc.identifier.doi10.17863/CAM.30546
dcterms.dateAccepted2018-05-14
rioxxterms.versionofrecord10.1038/s41467-018-04679-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2018-05-14
dc.contributor.orcidMaxwell, Patrick [0000-0002-0338-2679]
dc.identifier.eissn2041-1723
dc.publisher.urlhttps://www.nature.com/articles/s41467-018-04679-7
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (096956/Z/11/Z)
cam.issuedOnline2018-07-02
dc.identifier.urlhttps://www.nature.com/articles/s41467-018-04679-7
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International