Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation

Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation

I-Chun Tai,1–3 Yao-Hsien Wang,3 Chung-Hwan Chen,3,4 Shu-Chun Chuang,3 Je-Ken Chang,3–5 Mei-Ling Ho1–3,6 1Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Physiology, College of Medicine, Kaohsiung Medical Universi...

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Autores principales: Tai IC, Wang YH, Chen CH, Chuang SC, Chang JK, Ho ML
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2015
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Medicine (General)
R5-920
Acceso en línea:https://doaj.org/article/194e65feee534d999a20bace0e255638
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spelling oai:doaj.org-article:194e65feee534d999a20bace0e2556382021-12-02T01:52:16ZSimvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation1178-2013https://doaj.org/article/194e65feee534d999a20bace0e2556382015-09-01T00:00:00Zhttps://www.dovepress.com/simvastatin-enhances-rhoactincell-rigidity-pathway-contributing-to-mes-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013I-Chun Tai,1–3 Yao-Hsien Wang,3 Chung-Hwan Chen,3,4 Shu-Chun Chuang,3 Je-Ken Chang,3–5 Mei-Ling Ho1–3,6 1Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 5Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 6Department of Marine Biotechnology and Resources, National Sun Yat-sen UniVersity, Kaohsiung, Taiwan Abstract: Recent studies have indicated that statins induce osteogenic differentiation both in vitro and in vivo. The molecular mechanism of statin-stimulated osteogenesis is unknown. Activation of RhoA signaling increases cytoskeletal tension, which plays a crucial role in the osteogenic differentiation of mesenchymal stem cells. We thus hypothesized that RhoA signaling is involved in simvastatin-induced osteogenesis in bone marrow mesenchymal stem cells. We found that although treatment with simvastatin shifts localization of RhoA protein from the membrane to the cytosol, the treatment still activates RhoA dose-dependently because it reduces the association with RhoGDIα. Simvastatin also increased the expression of osteogenic proteins, density of actin filament, the number of focal adhesions, and cellular tension. Furthermore, disrupting actin cytoskeleton or decreasing cell rigidity by using chemical agents reduced simvastatin-induced osteogenic differentiation. In vivo study also confirms that density of actin filament is increased in simvastatin-induced ectopic bone formation. Our study is the first to demonstrate that maintaining intact actin cytoskeletons and enhancing cell rigidity are crucial in simvastatin-induced osteogenesis. The results suggested that simvastatin, which is an osteoinductive factor and acts by increasing actin filament organization and cell rigidity combined with osteoconductive biomaterials, may benefit stem-cell-based bone regeneration. Keywords: statins, RhoA, cytoskeleton, osteogenic differentiation, BMSCsTai ICWang YHChen CHChuang SCChang JKHo MLDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2015, Iss default, Pp 5881-5894 (2015)
institution DOAJ
collection DOAJ
language EN
topic Medicine (General)
R5-920
spellingShingle Medicine (General)
R5-920
Tai IC
Wang YH
Chen CH
Chuang SC
Chang JK
Ho ML
Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
description I-Chun Tai,1–3 Yao-Hsien Wang,3 Chung-Hwan Chen,3,4 Shu-Chun Chuang,3 Je-Ken Chang,3–5 Mei-Ling Ho1–3,6 1Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 5Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 6Department of Marine Biotechnology and Resources, National Sun Yat-sen UniVersity, Kaohsiung, Taiwan Abstract: Recent studies have indicated that statins induce osteogenic differentiation both in vitro and in vivo. The molecular mechanism of statin-stimulated osteogenesis is unknown. Activation of RhoA signaling increases cytoskeletal tension, which plays a crucial role in the osteogenic differentiation of mesenchymal stem cells. We thus hypothesized that RhoA signaling is involved in simvastatin-induced osteogenesis in bone marrow mesenchymal stem cells. We found that although treatment with simvastatin shifts localization of RhoA protein from the membrane to the cytosol, the treatment still activates RhoA dose-dependently because it reduces the association with RhoGDIα. Simvastatin also increased the expression of osteogenic proteins, density of actin filament, the number of focal adhesions, and cellular tension. Furthermore, disrupting actin cytoskeleton or decreasing cell rigidity by using chemical agents reduced simvastatin-induced osteogenic differentiation. In vivo study also confirms that density of actin filament is increased in simvastatin-induced ectopic bone formation. Our study is the first to demonstrate that maintaining intact actin cytoskeletons and enhancing cell rigidity are crucial in simvastatin-induced osteogenesis. The results suggested that simvastatin, which is an osteoinductive factor and acts by increasing actin filament organization and cell rigidity combined with osteoconductive biomaterials, may benefit stem-cell-based bone regeneration. Keywords: statins, RhoA, cytoskeleton, osteogenic differentiation, BMSCs
format article
author Tai IC
Wang YH
Chen CH
Chuang SC
Chang JK
Ho ML
author_facet Tai IC
Wang YH
Chen CH
Chuang SC
Chang JK
Ho ML
author_sort Tai IC
title Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
title_short Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
title_full Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
title_fullStr Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
title_full_unstemmed Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
title_sort simvastatin enhances rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
publisher Dove Medical Press
publishDate 2015
url https://doaj.org/article/194e65feee534d999a20bace0e255638
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AT wangyh simvastatinenhancesrhoactincellrigiditypathwaycontributingtomesenchymalstemcellsrsquonbsposteogenicdifferentiation
AT chench simvastatinenhancesrhoactincellrigiditypathwaycontributingtomesenchymalstemcellsrsquonbsposteogenicdifferentiation
AT chuangsc simvastatinenhancesrhoactincellrigiditypathwaycontributingtomesenchymalstemcellsrsquonbsposteogenicdifferentiation
AT changjk simvastatinenhancesrhoactincellrigiditypathwaycontributingtomesenchymalstemcellsrsquonbsposteogenicdifferentiation
AT homl simvastatinenhancesrhoactincellrigiditypathwaycontributingtomesenchymalstemcellsrsquonbsposteogenicdifferentiation
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