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Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells.
J Bone Miner Res. 2011 Apr; 26(4):730-8.JB

Abstract

Mesenchymal stem cells (MSCs) cultured on extracellular matrices with different stiffness have been shown to possess diverse lineage commitment owing to the extracellular mechanical stimuli sensed by the cells. The aim of this study was to further delineate how matrix stiffness affects intracellular signaling through the mechanotransducers Rho kinase (ROCK) and focal adhesion kinase (FAK) and subsequently regulates the osteogenic phenotype of MSCs. MSCs were cultured in osteogenic medium on tunable polyacrylamide hydrogels coated with type I collagen with elasticities corresponding to Young's modulus of 7.0 ± 1.2 and 42.1 ± 3.2 kPa. Osteogenic differentiation was increased on stiffer matrices, as evident by type I collagen, osteocalcin, and Runx2 gene expressions and alizarin red S staining for mineralization. Western blot analysis demonstrated an increase in kinase activities of ROCK, FAK, and ERK1/2 on stiffer matrices. Inhibition of FAK, an important mediator of osteogenic differentiation, and inhibition of ROCK, a known mechanotransducer of matrix stiffness during osteogenesis, resulted in decreased expression of osteogenic markers during osteogenic induction. In addition, FAK affects osteogenic differentiation through ERK1/2, whereas ROCK regulates both FAK and ERK1/2. Furthermore, α(2)-integrin was upregulated on stiffer matrices during osteogenic induction, and its knockdown by siRNA downregulated the osteogenic phenotype through ROCK, FAK, and ERK1/2. Taken together, our results provide evidence that the matrix rigidity affects the osteogenic outcome of MSCs through mechanotransduction events that are mediated by α(2)-integrin.

Authors+Show Affiliations

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20939067

Citation

Shih, Yu-Ru V., et al. "Matrix Stiffness Regulation of Integrin-mediated Mechanotransduction During Osteogenic Differentiation of Human Mesenchymal Stem Cells." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 26, no. 4, 2011, pp. 730-8.
Shih YR, Tseng KF, Lai HY, et al. Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells. J Bone Miner Res. 2011;26(4):730-8.
Shih, Y. R., Tseng, K. F., Lai, H. Y., Lin, C. H., & Lee, O. K. (2011). Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 26(4), 730-8. https://doi.org/10.1002/jbmr.278
Shih YR, et al. Matrix Stiffness Regulation of Integrin-mediated Mechanotransduction During Osteogenic Differentiation of Human Mesenchymal Stem Cells. J Bone Miner Res. 2011;26(4):730-8. PubMed PMID: 20939067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells. AU - Shih,Yu-Ru V, AU - Tseng,Kuo-Fung, AU - Lai,Hsiu-Yu, AU - Lin,Chi-Hung, AU - Lee,Oscar K, PY - 2010/10/13/entrez PY - 2010/10/13/pubmed PY - 2011/9/3/medline SP - 730 EP - 8 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 26 IS - 4 N2 - Mesenchymal stem cells (MSCs) cultured on extracellular matrices with different stiffness have been shown to possess diverse lineage commitment owing to the extracellular mechanical stimuli sensed by the cells. The aim of this study was to further delineate how matrix stiffness affects intracellular signaling through the mechanotransducers Rho kinase (ROCK) and focal adhesion kinase (FAK) and subsequently regulates the osteogenic phenotype of MSCs. MSCs were cultured in osteogenic medium on tunable polyacrylamide hydrogels coated with type I collagen with elasticities corresponding to Young's modulus of 7.0 ± 1.2 and 42.1 ± 3.2 kPa. Osteogenic differentiation was increased on stiffer matrices, as evident by type I collagen, osteocalcin, and Runx2 gene expressions and alizarin red S staining for mineralization. Western blot analysis demonstrated an increase in kinase activities of ROCK, FAK, and ERK1/2 on stiffer matrices. Inhibition of FAK, an important mediator of osteogenic differentiation, and inhibition of ROCK, a known mechanotransducer of matrix stiffness during osteogenesis, resulted in decreased expression of osteogenic markers during osteogenic induction. In addition, FAK affects osteogenic differentiation through ERK1/2, whereas ROCK regulates both FAK and ERK1/2. Furthermore, α(2)-integrin was upregulated on stiffer matrices during osteogenic induction, and its knockdown by siRNA downregulated the osteogenic phenotype through ROCK, FAK, and ERK1/2. Taken together, our results provide evidence that the matrix rigidity affects the osteogenic outcome of MSCs through mechanotransduction events that are mediated by α(2)-integrin. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/20939067/Matrix_stiffness_regulation_of_integrin_mediated_mechanotransduction_during_osteogenic_differentiation_of_human_mesenchymal_stem_cells_ L2 - https://doi.org/10.1002/jbmr.278 DB - PRIME DP - Unbound Medicine ER -