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Alpha-5 Integrin Mediates Simvastatin-Induced Osteogenesis of Bone Marrow Mesenchymal Stem Cells

1,2, 3,4,5, 3,5,6, 3,5,6,7,8, 3,4,9,10,11 and 3,5,6,8,*
1
Department of Nursing, Asia University, Taichung 413, Taiwan
2
Department of Medical Research, China Medical University Hospital, China Medical University,Taichung 404, Taiwan
3
Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
4
Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
5
Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
6
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
7
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan
8
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
9
Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
10
Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 801, Taiwan
11
Division of Adult Reconstruction Surgery, Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(3), 506; https://doi.org/10.3390/ijms20030506
Received: 12 December 2018 / Revised: 17 January 2019 / Accepted: 20 January 2019 / Published: 24 January 2019
(This article belongs to the Special Issue Osteoblasts and Osteocytes)
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Abstract

Simvastatin (SVS) promotes the osteogenic differentiation of mesenchymal stem cells (MSCs) and has been studied for MSC-based bone regeneration. However, the mechanism underlying SVS-induced osteogenesis is not well understood. We hypothesize that α5 integrin mediates SVS-induced osteogenic differentiation. Bone marrow MSCs (BMSCs) derived from BALB/C mice, referred to as D1 cells, were used. Alizarin red S (calcium deposition) and alkaline phosphatase (ALP) staining were used to evaluate SVS-induced osteogenesis of D1 cells. The mRNA expression levels of α5 integrin and osteogenic marker genes (bone morphogenetic protein-2 (BMP-2), runt-related transcription factor 2 (Runx2), collagen type I, ALP and osteocalcin (OC)) were detected using quantitative real-time PCR. Surface-expressed α5 integrin was detected using flow cytometry analysis. Protein expression levels of α5 integrin and phosphorylated focal adhesion kinase (p-FAK), which is downstream of α5 integrin, were detected using Western blotting. siRNA was used to deplete the expression of α5 integrin in D1 cells. The results showed that SVS dose-dependently enhanced the gene expression levels of osteogenic marker genes as well as subsequent ALP activity and calcium deposition in D1 cells. Upregulated p-FAK was accompanied by an increased protein expression level of α5 integrin after SVS treatment. Surface-expressed α5 integrin was also upregulated after SVS treatment. Depletion of α5 integrin expression significantly suppressed SVS-induced osteogenic gene expression levels, ALP activity, and calcium deposition in D1 cells. These results identify a critical role of α5 integrin in SVS-induced osteogenic differentiation of BMSCs, which may suggest a therapeutic strategy to modulate α5 integrin/FAK signaling to promote MSC-based bone regeneration. View Full-Text
Keywords: bone regeneration; bone marrow mesenchymal stem cells (BMSCs); simvastatin (SVS); osteogenic differentiation; α5 integrin bone regeneration; bone marrow mesenchymal stem cells (BMSCs); simvastatin (SVS); osteogenic differentiation; α5 integrin
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Shao, P.-L.; Wu, S.-C.; Lin, Z.-Y.; Ho, M.-L.; Chen, C.-H.; Wang, C.-Z. Alpha-5 Integrin Mediates Simvastatin-Induced Osteogenesis of Bone Marrow Mesenchymal Stem Cells. Int. J. Mol. Sci. 2019, 20, 506.

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