Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages
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. Tie2 CRE/+ ;Bmp2 tg/tg mi...
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| Veröffentlicht in: | Cell death & disease 2021-07, Vol.12 (8), p.729-729, Article 729 |
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| creator | Prados, Belén del Toro, Raquel MacGrogan, Donal Gómez-Apiñániz, Paula Papoutsi, Tania Muñoz-Cánoves, Pura Méndez-Ferrer, Simón de la Pompa, José Luis |
| description | 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.
Tie2
CRE/+
;Bmp2
tg/tg
mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably,
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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,
Tie2
CRE/+
;Bmp2
tg/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. |
| doi_str_mv | 10.1038/s41419-021-04003-0 |
| format | Article |
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Tie2
promoter.
Tie2
CRE/+
;Bmp2
tg/tg
mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably,
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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,
Tie2
CRE/+
;Bmp2
tg/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.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-021-04003-0</identifier><identifier>PMID: 34294700</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 13/51 ; 59/78 ; 631/136/815/817 ; 631/532/1542 ; 631/80/304 ; 64/60 ; 96/106 ; Animals ; Antibodies ; Aortic valve ; Aortic Valve - diagnostic imaging ; Aortic Valve - pathology ; Aortic Valve - physiopathology ; Biochemistry ; Biomedical and Life Sciences ; Bone diseases ; Bone growth ; Bone marrow ; Bone Marrow Transplantation ; Bone morphogenetic protein 2 ; Bone Morphogenetic Protein 2 - blood ; Bone Morphogenetic Protein 2 - metabolism ; Bone morphogenetic proteins ; Calcinosis - diagnostic imaging ; Calcinosis - pathology ; Calcinosis - physiopathology ; Cell Biology ; Cell Culture ; Cell Lineage ; Chondrogenesis ; Colonization ; Endochondral bone ; Endothelial Cells - metabolism ; Fibroblasts ; Glial stem cells ; Hematopoiesis ; Hematopoietic stem cells ; Hematopoietic Stem Cells - metabolism ; Homeostasis ; Immunology ; Inflammation ; Kaplan-Meier Estimate ; Life Sciences ; Life Sciences & Biomedicine ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle Cells - pathology ; Musculoskeletal system ; Myositis ossificans ; Ossification (ectopic) ; Ossification, Heterotopic - blood ; Ossification, Heterotopic - diagnostic imaging ; Ossification, Heterotopic - metabolism ; Ossification, Heterotopic - pathology ; Osteogenesis ; Osteoprogenitor cells ; Progenitor cells ; Receptor, TIE-2 - metabolism ; Science & Technology ; Skeletal muscle ; Stem cell transplantation ; Tomography, X-Ray Computed ; Transgenic animals ; Transgenic mice</subject><ispartof>Cell death & disease, 2021-07, Vol.12 (8), p.729-729, Article 729</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>11</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000683355100004</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c540t-8650f8cb31c0817fd7f3870ce84d0f66dffaf3d6116ab520ae2d484d907237f93</citedby><cites>FETCH-LOGICAL-c540t-8650f8cb31c0817fd7f3870ce84d0f66dffaf3d6116ab520ae2d484d907237f93</cites><orcidid>0000-0002-9805-9988 ; 0000-0003-2808-8422 ; 0000-0002-7533-9047 ; 0000-0001-6240-5626 ; 0000-0001-6761-7265 ; 0000-0002-1379-7990 ; 0000-0001-6393-7253</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298441/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298441/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2116,27931,27932,39265,41127,42196,51583,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34294700$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Prados, Belén</creatorcontrib><creatorcontrib>del Toro, Raquel</creatorcontrib><creatorcontrib>MacGrogan, Donal</creatorcontrib><creatorcontrib>Gómez-Apiñániz, Paula</creatorcontrib><creatorcontrib>Papoutsi, Tania</creatorcontrib><creatorcontrib>Muñoz-Cánoves, Pura</creatorcontrib><creatorcontrib>Méndez-Ferrer, Simón</creatorcontrib><creatorcontrib>de la Pompa, José Luis</creatorcontrib><title>Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>CELL DEATH DIS</addtitle><addtitle>Cell Death Dis</addtitle><description>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.
Tie2
CRE/+
;Bmp2
tg/tg
mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably,
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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,
Tie2
CRE/+
;Bmp2
tg/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.</description><subject>13/31</subject><subject>13/51</subject><subject>59/78</subject><subject>631/136/815/817</subject><subject>631/532/1542</subject><subject>631/80/304</subject><subject>64/60</subject><subject>96/106</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Aortic valve</subject><subject>Aortic Valve - diagnostic imaging</subject><subject>Aortic Valve - pathology</subject><subject>Aortic Valve - physiopathology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Bone diseases</subject><subject>Bone growth</subject><subject>Bone marrow</subject><subject>Bone Marrow Transplantation</subject><subject>Bone morphogenetic protein 2</subject><subject>Bone Morphogenetic Protein 2 - blood</subject><subject>Bone Morphogenetic Protein 2 - metabolism</subject><subject>Bone morphogenetic proteins</subject><subject>Calcinosis - diagnostic imaging</subject><subject>Calcinosis - pathology</subject><subject>Calcinosis - physiopathology</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Lineage</subject><subject>Chondrogenesis</subject><subject>Colonization</subject><subject>Endochondral bone</subject><subject>Endothelial Cells - metabolism</subject><subject>Fibroblasts</subject><subject>Glial stem cells</subject><subject>Hematopoiesis</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Homeostasis</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Kaplan-Meier Estimate</subject><subject>Life Sciences</subject><subject>Life Sciences & Biomedicine</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Muscle Cells - pathology</subject><subject>Musculoskeletal system</subject><subject>Myositis ossificans</subject><subject>Ossification (ectopic)</subject><subject>Ossification, Heterotopic - 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diagnostic imaging</topic><topic>Aortic Valve - pathology</topic><topic>Aortic Valve - physiopathology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Bone diseases</topic><topic>Bone growth</topic><topic>Bone marrow</topic><topic>Bone Marrow Transplantation</topic><topic>Bone morphogenetic protein 2</topic><topic>Bone Morphogenetic Protein 2 - blood</topic><topic>Bone Morphogenetic Protein 2 - metabolism</topic><topic>Bone morphogenetic proteins</topic><topic>Calcinosis - diagnostic imaging</topic><topic>Calcinosis - pathology</topic><topic>Calcinosis - physiopathology</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Lineage</topic><topic>Chondrogenesis</topic><topic>Colonization</topic><topic>Endochondral bone</topic><topic>Endothelial Cells - metabolism</topic><topic>Fibroblasts</topic><topic>Glial stem cells</topic><topic>Hematopoiesis</topic><topic>Hematopoietic stem cells</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>Homeostasis</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Kaplan-Meier Estimate</topic><topic>Life Sciences</topic><topic>Life Sciences & Biomedicine</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Muscle Cells - pathology</topic><topic>Musculoskeletal system</topic><topic>Myositis ossificans</topic><topic>Ossification (ectopic)</topic><topic>Ossification, Heterotopic - blood</topic><topic>Ossification, Heterotopic - diagnostic imaging</topic><topic>Ossification, Heterotopic - metabolism</topic><topic>Ossification, Heterotopic - pathology</topic><topic>Osteogenesis</topic><topic>Osteoprogenitor cells</topic><topic>Progenitor cells</topic><topic>Receptor, TIE-2 - metabolism</topic><topic>Science & Technology</topic><topic>Skeletal muscle</topic><topic>Stem cell transplantation</topic><topic>Tomography, X-Ray Computed</topic><topic>Transgenic animals</topic><topic>Transgenic mice</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Prados, Belén</creatorcontrib><creatorcontrib>del Toro, Raquel</creatorcontrib><creatorcontrib>MacGrogan, Donal</creatorcontrib><creatorcontrib>Gómez-Apiñániz, Paula</creatorcontrib><creatorcontrib>Papoutsi, Tania</creatorcontrib><creatorcontrib>Muñoz-Cánoves, Pura</creatorcontrib><creatorcontrib>Méndez-Ferrer, Simón</creatorcontrib><creatorcontrib>de la Pompa, José Luis</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Prados, Belén</au><au>del Toro, Raquel</au><au>MacGrogan, Donal</au><au>Gómez-Apiñániz, Paula</au><au>Papoutsi, Tania</au><au>Muñoz-Cánoves, Pura</au><au>Méndez-Ferrer, Simón</au><au>de la Pompa, José Luis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><stitle>CELL DEATH DIS</stitle><addtitle>Cell Death Dis</addtitle><date>2021-07-22</date><risdate>2021</risdate><volume>12</volume><issue>8</issue><spage>729</spage><epage>729</epage><pages>729-729</pages><artnum>729</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><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.
Tie2
CRE/+
;Bmp2
tg/tg
mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably,
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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
Tie2
CRE/+
;Bmp2
tg/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,
Tie2
CRE/+
;Bmp2
tg/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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34294700</pmid><doi>10.1038/s41419-021-04003-0</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-9805-9988</orcidid><orcidid>https://orcid.org/0000-0003-2808-8422</orcidid><orcidid>https://orcid.org/0000-0002-7533-9047</orcidid><orcidid>https://orcid.org/0000-0001-6240-5626</orcidid><orcidid>https://orcid.org/0000-0001-6761-7265</orcidid><orcidid>https://orcid.org/0000-0002-1379-7990</orcidid><orcidid>https://orcid.org/0000-0001-6393-7253</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2041-4889 |
| ispartof | Cell death & disease, 2021-07, Vol.12 (8), p.729-729, Article 729 |
| issn | 2041-4889 2041-4889 |
| language | eng |
| recordid | cdi_webofscience_primary_000683355100004 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Nature Free; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; PubMed Central; Springer Nature OA/Free Journals |
| subjects | 13/31 13/51 59/78 631/136/815/817 631/532/1542 631/80/304 64/60 96/106 Animals Antibodies Aortic valve Aortic Valve - diagnostic imaging Aortic Valve - pathology Aortic Valve - physiopathology Biochemistry Biomedical and Life Sciences Bone diseases Bone growth Bone marrow Bone Marrow Transplantation Bone morphogenetic protein 2 Bone Morphogenetic Protein 2 - blood Bone Morphogenetic Protein 2 - metabolism Bone morphogenetic proteins Calcinosis - diagnostic imaging Calcinosis - pathology Calcinosis - physiopathology Cell Biology Cell Culture Cell Lineage Chondrogenesis Colonization Endochondral bone Endothelial Cells - metabolism Fibroblasts Glial stem cells Hematopoiesis Hematopoietic stem cells Hematopoietic Stem Cells - metabolism Homeostasis Immunology Inflammation Kaplan-Meier Estimate Life Sciences Life Sciences & Biomedicine Mice, Inbred C57BL Mice, Transgenic Muscle Cells - pathology Musculoskeletal system Myositis ossificans Ossification (ectopic) Ossification, Heterotopic - blood Ossification, Heterotopic - diagnostic imaging Ossification, Heterotopic - metabolism Ossification, Heterotopic - pathology Osteogenesis Osteoprogenitor cells Progenitor cells Receptor, TIE-2 - metabolism Science & Technology Skeletal muscle Stem cell transplantation Tomography, X-Ray Computed Transgenic animals Transgenic mice |
| title | Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-04T02%3A39%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Heterotopic%20ossification%20in%20mice%20overexpressing%20Bmp2%20in%20Tie2+%20lineages&rft.jtitle=Cell%20death%20&%20disease&rft.au=Prados,%20Bel%C3%A9n&rft.date=2021-07-22&rft.volume=12&rft.issue=8&rft.spage=729&rft.epage=729&rft.pages=729-729&rft.artnum=729&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/s41419-021-04003-0&rft_dat=%3Cproquest_webof%3E2555109671%3C/proquest_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2554122351&rft_id=info:pmid/34294700&rft_doaj_id=oai_doaj_org_article_d4a09a541c4243abba6f5b49417ad8d7&rfr_iscdi=true |