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Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages

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dc.contributor.author Prados, Belén
dc.contributor.author Del Toro, Raquel
dc.contributor.author MacGrogan, Donal
dc.contributor.author Gómez Apiñániz, Paula
dc.contributor.author Papoutsi, Tania
dc.contributor.author Muñoz Cánoves, Pura, 1962-
dc.contributor.author Méndez Ferrer, Simón
dc.contributor.author de la Pompa, José Luis
dc.date.accessioned 2021-10-08T06:03:53Z
dc.date.available 2021-10-08T06:03:53Z
dc.date.issued 2021
dc.identifier.citation Prados B, Del Toro R, MacGrogan D, Gómez-Apiñániz P, Papoutsi T, Muñoz-Cánoves P, Méndez-Ferrer S, de la Pompa JL. Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages. Cell Death Dis. 2021;12(8):729. DOI: 10.1038/s41419-021-04003-0
dc.identifier.issn 2041-4889
dc.identifier.uri http://hdl.handle.net/10230/48593
dc.description.abstract Bone morphogenetic protein (Bmp) signaling is critical for organismal development and homeostasis. To elucidate Bmp2 function in the vascular/hematopoietic lineages we generated a new transgenic mouse line in which ectopic Bmp2 expression is controlled by the Tie2 promoter. Tie2CRE/+;Bmp2tg/tg mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably, Tie2CRE/+;Bmp2tg/tg mice develop extensive soft tissue bone formation typical of acquired forms of heterotopic ossification (HO) and genetic bone disorders, such as Fibrodysplasia Ossificans Progressiva (FOP). Ectopic ossification in Tie2CRE/+;Bmp2tg/tg transgenic animals is accompanied by increased bone marrow hematopoietic, fibroblast and osteoblast precursors and circulating pro-inflammatory cells. Transplanting wild-type bone marrow hematopoietic stem cells into lethally irradiated Tie2CRE/+;Bmp2tg/tg mice significantly delays HO onset but does not prevent it. Moreover, transplanting Bmp2-transgenic bone marrow into wild-type recipients does not result in HO, but hematopoietic progenitors contribute to inflammation and ectopic bone marrow colonization rather than to endochondral ossification. Conversely, aberrant Bmp2 signaling activity is associated with fibroblast accumulation, skeletal muscle fiber damage, and expansion of a Tie2+ fibro-adipogenic precursor cell population, suggesting that ectopic bone derives from a skeletal muscle resident osteoprogenitor cell origin. Thus, Tie2CRE/+;Bmp2tg/tg mice recapitulate HO pathophysiology, and might represent a useful model to investigate therapies seeking to mitigate disorders associated with aberrant extra-skeletal bone formation.
dc.description.sponsorship Grants PID2019-104776RB-I00, SAF2016-78370-R, CB16/11/00399 (CIBER CV), and RD16/0011/0021 (TERCEL) from the Spanish Ministry of Science, Innovation, and Universities (MCIU) to JLDLP. The cost of this publication was supported in part with FEDER funds. The CNIC is supported by the MCIU and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The authors declare no competing interests.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Cell Death Dis. 2021;12(8):729
dc.rights © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41419-021-04003-0
dc.subject.keyword Central control of bone remodelling
dc.subject.keyword Haematopoietic stem cells
dc.subject.keyword Mechanisms of disease
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104776RB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-78370-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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