The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation

Mutations in MAN1, a protein of the nuclear envelope, cause bone phenotypes characterized by hyperostosis. The mechanism of this proosteogenic phenotype remains unknown. We increased and decreased MAN1 expression in mesenchymal stem cells (MSC) upon which standard osteogenic and adipogenic different...

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Autores:
Bermeo, Sandra
Al-Saedi, Ahmed
Kassem, Moustapha
Vidal, Christopher
Duque, Gustavo
Tipo de recurso:
Fecha de publicación:
2017
Institución:
Universidad Simón Bolívar
Repositorio:
Repositorio Digital USB
Idioma:
eng
OAI Identifier:
oai:bonga.unisimon.edu.co:20.500.12442/1897
Acceso en línea:
http://hdl.handle.net/20.500.12442/1897
Palabra clave:
Mesenchymal stem cells
Osteoblastogenesis
Adipogenesis
Man1
Lamin A
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License
Licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional
id USIMONBOL2_719b482c7df55fb3a287be2f67e3b2ad
oai_identifier_str oai:bonga.unisimon.edu.co:20.500.12442/1897
network_acronym_str USIMONBOL2
network_name_str Repositorio Digital USB
repository_id_str
dc.title.eng.fl_str_mv The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
title The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
spellingShingle The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
Mesenchymal stem cells
Osteoblastogenesis
Adipogenesis
Man1
Lamin A
title_short The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
title_full The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
title_fullStr The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
title_full_unstemmed The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
title_sort The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation
dc.creator.fl_str_mv Bermeo, Sandra
Al-Saedi, Ahmed
Kassem, Moustapha
Vidal, Christopher
Duque, Gustavo
dc.contributor.author.none.fl_str_mv Bermeo, Sandra
Al-Saedi, Ahmed
Kassem, Moustapha
Vidal, Christopher
Duque, Gustavo
dc.subject.eng.fl_str_mv Mesenchymal stem cells
Osteoblastogenesis
Adipogenesis
Man1
Lamin A
topic Mesenchymal stem cells
Osteoblastogenesis
Adipogenesis
Man1
Lamin A
description Mutations in MAN1, a protein of the nuclear envelope, cause bone phenotypes characterized by hyperostosis. The mechanism of this proosteogenic phenotype remains unknown. We increased and decreased MAN1 expression in mesenchymal stem cells (MSC) upon which standard osteogenic and adipogenic differentiation were performed. MAN1 knockdown increased osteogenesis and mineralization. In contrast, osteogenesis remained stable upon MAN1 overexpression. Regarding a mechanism, we found that low levels of MAN1 facilitated the nuclear accumulation of regulatory smads and smads-related complexes, with a concurrently high expression of nuclear b-Catenin. In addition, we found adipogenesis to be decreased in both conditions, although predominantly affected by MAN1 overexpression. Finally, lamin A, a protein of the nuclear envelope that regulates MSC differentiation, was unaffected by changes in MAN1. In conclusion, our studies demonstrated that lower levels of MAN1 in differentiating MSC are associated with higher osteogenesis and lower adipogenesis. High levels of MAN1 only affected adipogenesis. These effects could have an important role in the understanding of the role of the proteins of the nuclear envelope in bone formation. J. Cell. Biochem. 118: 4425–4435, 2017.
publishDate 2017
dc.date.issued.none.fl_str_mv 2017-04
dc.date.accessioned.none.fl_str_mv 2018-03-22T14:22:14Z
dc.date.available.none.fl_str_mv 2018-03-22T14:22:14Z
dc.type.eng.fl_str_mv article
dc.type.coar.fl_str_mv http://purl.org/coar/resource_type/c_6501
dc.identifier.issn.none.fl_str_mv 10974644
dc.identifier.uri.none.fl_str_mv http://hdl.handle.net/20.500.12442/1897
identifier_str_mv 10974644
url http://hdl.handle.net/20.500.12442/1897
dc.language.iso.eng.fl_str_mv eng
language eng
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_16ec
dc.rights.license.spa.fl_str_mv Licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional
rights_invalid_str_mv Licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional
http://purl.org/coar/access_right/c_16ec
dc.publisher.eng.fl_str_mv DeepDyve
dc.source.eng.fl_str_mv Journal of Cellular Biochemistry
dc.source.spa.fl_str_mv Vol. 118 (2017)
institution Universidad Simón Bolívar
dc.source.uri.none.fl_str_mv https://findanexpert.unimelb.edu.au/display/publicationS1205982
bitstream.url.fl_str_mv https://bonga.unisimon.edu.co/bitstreams/62730653-295e-45b2-a9da-9e0a09f812c4/download
bitstream.checksum.fl_str_mv 8a4605be74aa9ea9d79846c1fba20a33
bitstream.checksumAlgorithm.fl_str_mv MD5
repository.name.fl_str_mv DSpace UniSimon
repository.mail.fl_str_mv bibliotecas@biteca.com
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spelling Licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacionalhttp://purl.org/coar/access_right/c_16ecBermeo, Sandra5adcb3ad-0b9f-41f8-8a5f-a4d6086d31ef-1Al-Saedi, Ahmed8360b6cf-0120-4921-a9e0-b810c711f449-1Kassem, Moustapha30f1da86-97ed-4e99-964d-871151b01e88-1Vidal, Christopher82a7b1e1-9fd8-43c2-aed8-0cace338cbaf-1Duque, Gustavof99ef41b-e311-4165-bbc4-73e084153d5f-12018-03-22T14:22:14Z2018-03-22T14:22:14Z2017-0410974644http://hdl.handle.net/20.500.12442/1897Mutations in MAN1, a protein of the nuclear envelope, cause bone phenotypes characterized by hyperostosis. The mechanism of this proosteogenic phenotype remains unknown. We increased and decreased MAN1 expression in mesenchymal stem cells (MSC) upon which standard osteogenic and adipogenic differentiation were performed. MAN1 knockdown increased osteogenesis and mineralization. In contrast, osteogenesis remained stable upon MAN1 overexpression. Regarding a mechanism, we found that low levels of MAN1 facilitated the nuclear accumulation of regulatory smads and smads-related complexes, with a concurrently high expression of nuclear b-Catenin. In addition, we found adipogenesis to be decreased in both conditions, although predominantly affected by MAN1 overexpression. Finally, lamin A, a protein of the nuclear envelope that regulates MSC differentiation, was unaffected by changes in MAN1. In conclusion, our studies demonstrated that lower levels of MAN1 in differentiating MSC are associated with higher osteogenesis and lower adipogenesis. High levels of MAN1 only affected adipogenesis. These effects could have an important role in the understanding of the role of the proteins of the nuclear envelope in bone formation. J. Cell. Biochem. 118: 4425–4435, 2017.engDeepDyveJournal of Cellular BiochemistryVol. 118 (2017)https://findanexpert.unimelb.edu.au/display/publicationS1205982Mesenchymal stem cellsOsteoblastogenesisAdipogenesisMan1Lamin AThe Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiationarticlehttp://purl.org/coar/resource_type/c_6501Akter R, Rivas D, Geneau G, Drissi H, Duque G. 2009. Effect of lamin A/C knockdown on osteoblast differentiation and function. J Bone Miner Res 24:283–293.Andres V, Gonzalez JM. 2009. Role of A-type lamins in signaling, transcription, and chromatin organization. J Cell Biol 187:945–957.Bengtsson L. 2007. What MAN1 does to the smads—TGF beta/BMP signaling and the nuclear envelope. FEBS J 274:1374–1382.Bermeo S, Gunaratnam K, Duque G. 2014. Fat and bone interactions. Curr Osteoporos Rep 12:235–242.Bermeo S, Vidal C, Zhou H, Duque G. 2015. 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Eur J Dermatol 20:693–697.Caputo S, Couprie J, Duband-Goulet I, Konde E, Lin F, Braud S, Gondry M, Gilquin B, Worman HJ, Zinn-Justin S. 2006. The carboxyl-terminal nucleoplasmic region of MAN1 exhibits a DNA binding winged helix domain. J Biol Chem 281:18208–18215.Chen G, Deng C, Li YP. 2012. TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8:272–288.Cohen TV, Kosti O, Stewart CL. 2007. The nuclear envelope protein MAN1 regulates TGFbeta signaling and vasculogenesis in the embryonic yolk sac. Development 134:1385–1395.Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK, Wilson KL. 2005. The nuclear lamina comes of age. Nat Rev Mol Cell Biol 6:21–31.Heessen S, Fornerod M. 2007. The inner nuclear envelope as a transcription factor resting place. EMBO Rep 8:914–919.Hellemans J, Preobrazhenska O, Willaert A, Debeer P, Verdonk PC, Costa T, Janssens K, Menten B, Van Roy N, Vermeulen SJ, Savarirayan R, Van Hul W, Vanhoenacker F, Huylebroeck D, De Paepe A, Naeyaert JM, Vandesompele J, Speleman F, Verschueren K, Coucke PJ, Mortier GR. 2004. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke–Ollendorff syndrome and melorheostosis. Nat Genet 36:1213–1218.Ishimura A, Ng JK, Taira M, Young SG, Osada S. 2006. Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor beta signaling. Development 133:3919–3928.Javed A, Afzal F, Bae JS, Gutierrez S, Zaidi K, Pratap J, van Wijnen AJ, Stein JL, Stein GS, Lian JB. 2009. Specific residues of RUNX2 are obligatory for formation of BMP2-induced RUNX2-SMAD complex to promote osteoblast differentiation. 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Decreased bone formation and osteopenia in lamin a/c-deficient mice. PLoS ONE 6:e19313.Lin F, Morrison JM, Wu W, Worman HJ. 2005. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Hum Mol Genet 14:437–445.Lowery JW, Intini G, Gamer L, Lotinun S, Salazar VS, Ote S, Cox K, Baron R, Rosen V. 2015. Loss of BMPR2 leads to high bone mass due to increased osteoblast activity. J Cell Sci 128:1308–1315.Mansharamani M, Wilson KL. 2005. Direct binding of nuclear membrane protein MAN1 to emerin in vitro and two modes of binding to barrier-toautointegration factor. J Biol Chem 280:13863–13870.Mumm S, Wenkert D, Zhang X, McAlister WH, Mier RJ, Whyte MP. 2007. Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke–Ollendorff syndrome, but not sporadic melorheostosis. J Bone Miner Res 22:243–250.Pan D, Estevez-Salmeron LD, Stroschein SL, Zhu X, He J, Zhou S, Luo K. 2005. The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines. J Biol Chem 280: 15992–16001.Parnaik VK. 2008. Role of nuclear lamins in nuclear organization, cellular signaling, and inherited diseases. Int Rev Cell Mol Biol 266:157–206.Pei L, Tontonoz P. 2004. Fat’s loss is bone’s gain. J Clin Invest 113: 805–806.Pfaffl MW, Horgan GW, Dempfle L. 2002. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30:e36.Qiu W, Hu Y, AndQersen TE, Jafari A, Li N, Chen W, Kassem M. 2010. Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) regulates differentiation fate of human mesenchymal (stromal) stem cells through canonical Wnt signaling and C/EBP. J Biol Chem 285: 14438–14449.Rosen C, Bouxsein M. 2006. Mechanisms of disease: Is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol 2:35–43.Sabokbar A, Millett PJ, Myer B, Rushton N. 1994. A rapid, quantitative assay for measuring alkaline phosphatase activity in osteoblastic cells in vitro. Bone Miner 27:57–67.Sethe S, Scutt A, Stolzing A. 2006. Aging of mesenchymal stem cells. Ageing Res Rev 5:91–116.Shaklai S, Amariglio N, Rechavi G, Simon AJ. 2007. Gene silencing at the nuclear periphery. FEBS J 274:1383–1392.Tong J, Li W, Vidal C, Yeo LS, Fatkin D, Duque G. 2011. Lamin A/C deficiency is associated with fat infiltration of muscle and bone. Mech Ageing Dev 132:552–559.Vidal C, Bermeo S, Fatkin D, Duque G. 2012a. Role of the nuclear envelope in the pathogenesis of age-related bone loss and osteoporosis. BoneKEy Rep 1:62.Vidal C, Bermeo S, Li W, Huang D, Kremer R, Duque G. 2012b. Interferon gamma inhibits adipogenesis in vitro and prevents marrow fat infiltration in oophorectomized mice. 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J Cell Biochem 112:1651–1660.LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://bonga.unisimon.edu.co/bitstreams/62730653-295e-45b2-a9da-9e0a09f812c4/download8a4605be74aa9ea9d79846c1fba20a33MD5220.500.12442/1897oai:bonga.unisimon.edu.co:20.500.12442/18972019-04-11 21:51:29.826metadata.onlyhttps://bonga.unisimon.edu.coDSpace UniSimonbibliotecas@biteca.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