Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo
Sclerostin is a protein secreted by osteocytes that is encoded by the SOST gene; it decreases bone formation by reducing osteoblast differentiation through inhibition of the Wnt signaling pathway. Silencing the SOST gene using RNA interference (RNAi) could therefore be an effective way to treat oste...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117300872 |
| _version_ | 1811344134027345920 |
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| author | Genc Basha Mina Ordobadi Wilder R Scott Andrew Cottle Yan Liu Haitang Wang Pieter R Cullis |
| author_facet | Genc Basha Mina Ordobadi Wilder R Scott Andrew Cottle Yan Liu Haitang Wang Pieter R Cullis |
| author_sort | Genc Basha |
| collection | DOAJ |
| description | Sclerostin is a protein secreted by osteocytes that is encoded by the SOST gene; it decreases bone formation by reducing osteoblast differentiation through inhibition of the Wnt signaling pathway. Silencing the SOST gene using RNA interference (RNAi) could therefore be an effective way to treat osteoporosis. Here, we investigate the utility of lipid nanoparticle (LNP) formulations of siRNA to silence the SOST gene in vitro and in vivo. It is shown that primary mouse embryonic fibroblasts (MEF) provide a useful model system in which the SOST gene can be induced by incubation in osteogenic media, allowing development of optimized SOST siRNA for silencing the SOST gene. Incubation of MEF cells with LNP containing optimized SOST siRNA produced significant, prolonged knockdown of the induced SOST gene in vitro, which was associated with an increase in osteogenic markers. Intravenous (i.v.) administration of LNP containing SOST siRNA to mice showed significant accumulation of LNP in osteocytes in compact bone, depletion of SOST mRNA and subsequent reduction of circulating sclerostin protein, establishing the potential utility for LNP siRNA systems to promote bone formation. |
| first_indexed | 2024-04-13T19:42:20Z |
| format | Article |
| id | doaj.art-8331dfcc428d4acabc44738968af0a1f |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-13T19:42:20Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-8331dfcc428d4acabc44738968af0a1f2022-12-22T02:32:51ZengElsevierMolecular Therapy: Nucleic Acids2162-25312016-01-015C10.1038/mtna.2016.68Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In VivoGenc Basha0Mina Ordobadi1Wilder R Scott2Andrew Cottle3Yan Liu4Haitang Wang5Pieter R Cullis6NanoMedicines Research Group, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaNanoMedicines Research Group, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaDepartment of Cellular and Physiological Sciences, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, CanadaNanoMedicines Research Group, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaNanoMedicines Research Group, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaNanoMedicines Research Group, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaNanoMedicines Research Group, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaSclerostin is a protein secreted by osteocytes that is encoded by the SOST gene; it decreases bone formation by reducing osteoblast differentiation through inhibition of the Wnt signaling pathway. Silencing the SOST gene using RNA interference (RNAi) could therefore be an effective way to treat osteoporosis. Here, we investigate the utility of lipid nanoparticle (LNP) formulations of siRNA to silence the SOST gene in vitro and in vivo. It is shown that primary mouse embryonic fibroblasts (MEF) provide a useful model system in which the SOST gene can be induced by incubation in osteogenic media, allowing development of optimized SOST siRNA for silencing the SOST gene. Incubation of MEF cells with LNP containing optimized SOST siRNA produced significant, prolonged knockdown of the induced SOST gene in vitro, which was associated with an increase in osteogenic markers. Intravenous (i.v.) administration of LNP containing SOST siRNA to mice showed significant accumulation of LNP in osteocytes in compact bone, depletion of SOST mRNA and subsequent reduction of circulating sclerostin protein, establishing the potential utility for LNP siRNA systems to promote bone formation.http://www.sciencedirect.com/science/article/pii/S2162253117300872bone formationlipid nanoparticlessclerostinsiRNA |
| spellingShingle | Genc Basha Mina Ordobadi Wilder R Scott Andrew Cottle Yan Liu Haitang Wang Pieter R Cullis Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo Molecular Therapy: Nucleic Acids bone formation lipid nanoparticles sclerostin siRNA |
| title | Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo |
| title_full | Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo |
| title_fullStr | Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo |
| title_full_unstemmed | Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo |
| title_short | Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo |
| title_sort | lipid nanoparticle delivery of sirna to osteocytes leads to effective silencing of sost and inhibition of sclerostin in vivo |
| topic | bone formation lipid nanoparticles sclerostin siRNA |
| url | http://www.sciencedirect.com/science/article/pii/S2162253117300872 |
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