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Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

2011-11Journal article Open access
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dc.contributor.authorWillems, Brecht A.
dc.contributor.authorFurmanik, Malgorzata
dc.contributor.authorCaron, Marjolein M. J.
dc.contributor.authorChatrou, Martijn L. L.
dc.contributor.authorKusters, Dennis H. M.
dc.contributor.authorWelting, Tim J. M.
dc.contributor.authorStock, Michael
dc.contributor.authorRafael, Marta S.
dc.contributor.authorViegas, Carla S. B.
dc.contributor.authorSimes, Dina C.
dc.contributor.authorVermeer, Cees
dc.contributor.authorReutelingsperger, Chris P. M.
dc.contributor.authorSchurgers, Leon J.
dc.date.accessioned2018-12-07T14:57:54Z
dc.date.available2018-12-07T14:57:54Z
dc.date.issued2011-11
dc.description.abstractVascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.
dc.description.sponsorshipNWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1038/s41598-018-23353-y
dc.identifier.issn2045-2322
dc.identifier.urihttp://hdl.handle.net/10400.1/11756
dc.language.isoeng
dc.peerreviewedyes
dc.publisherNature Publishing Group
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectChronic kidney-disease
dc.subjectGla-rich protein
dc.subjectHuman atherosclerotic plaques
dc.subjectVitamin-K
dc.subjectPhenotypic modulation
dc.subjectBone-formation
dc.subjectExpression
dc.subjectMineralization
dc.subjectDifferentiation
dc.subjectCarboxylation
dc.titleUcma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F70277%2F2010/PT
oaire.citation.startPage4961
oaire.citation.titleScientific Reports
oaire.citation.volume8
oaire.fundingStreamSFRH
person.familyNameRafael
person.familyNameViegas
person.familyNameSimes
person.givenNameMarta
person.givenNameCarla
person.givenNameDina
person.identifier.ciencia-id1C10-BF17-0DD7
person.identifier.ciencia-idC414-F596-EEC6
person.identifier.orcid0000-0002-5518-9790
person.identifier.orcid0000-0002-5765-3665
person.identifier.orcid0000-0002-5145-4753
person.identifier.ridN-6695-2014
person.identifier.ridN-2789-2014
person.identifier.scopus-author-id15078212800
person.identifier.scopus-author-id8656310300
person.identifier.scopus-author-id7201884723
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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relation.isAuthorOfPublication33984b3c-ffac-477a-896a-ddbf7aced4e3
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