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ECM Compliance Regulates Osteogenesis by Influencing MAPK Signaling Downstream of RhoA and ROCK
Open accessAbstract
The compliance of the extracellular matrix (ECM) regulates osteogenic differentiation by modulating extracellular signal-regulated kinase (ERK) activity. However, the molecular mechanism linking ECM compliance to the ERK-mitogen-activated protein kinase (MAPK) pathway remains unclear. Furthermore, RhoA has been widely implicated in integrin-mediated signaling and mechanotransduction. We studied the relationship between RhoA and ERK-MAPK signaling to determine their roles in the regulation of osteogenesis by ECM compliance. Inhibition of RhoA and ROCK in MC3T3-E1 pre-osteoblasts cultured on substrates of varying compliance reduced ERK activity, whereas constitutively active RhoA enhanced it. The expression of RUNX2, a potent osteogenic transcription factor, was increased on stiffer matrices and correlated with elevated ERK activity. Inhibition of RhoA, ROCK, or the MAPK pathway diminished RUNX2 activity and delayed the onset of osteogenesis as shown by altered osteocalcin (OCN) and bone sialoprotein (BSP) gene expression, alkaline phosphatase (ALP) activity, and matrix mineralization. These data establish that one possible mechanism by which ECM rigidity regulates osteogenic differentiation involves MAPK activation downstream of the RhoA-ROCK signaling pathway.
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Cites
Matrix elasticity directs stem cell lineage specification
Engler, A. J., Sen, S., Sweeney, H. L., & Discher, D. E. (2006) · Cell · doi:10.1016/j.cell.2006.06.044 · Cited by 13,915
Myotubes differentiate optimally on substrates with tissue-like stiffness
Engler, A. J., Griffin, M. A., Sen, S., Bönnemann, C. G., Sweeney, H. L., & Discher, D. E. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200405004 · Cited by 1,743
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Mechanical regulation of bone remodeling
Wang, L., You, X., Zhang, L., Zhang, C., & Zou, W. (2022) · Bone Research · doi:10.1038/s41413-022-00190-4 · Cited by 641
Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation
Huebsch, N., Lippens, E., Lee, K., Mehta, M., Koshy, S. T., Darnell, M. C., Desai, R. M., Madl, C. M., Xu, M., Zhao, X., et al. (2015) · Nature Materials · doi:10.1038/nmat4407 · Cited by 521
Boning up on Wolff's Law: Mechanical regulation of the cells that make and maintain bone
Chen, J.-H., Liu, C., You, L., & Simmons, C. A. (2010) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2009.09.016 · Cited by 422
Transglutaminase Regulation of Cell Function
Eckert, R. L., Kaartinen, M. T., Nurminskaya, M., Belkin, A. M., Colak, G., Johnson, G. V. W., & Mehta, K. (2014) · Physiological Reviews · doi:10.1152/physrev.00019.2013 · Cited by 419
Synthetic Materials in the Study of Cell Response to Substrate Rigidity
Nemir, S., & West, J. L. (2010) · Annals of Biomedical Engineering · doi:10.1007/s10439-009-9811-1 · Cited by 318
Metadata
- Authors
- Khatiwala, C. B., Kim, P. D., Peyton, S. R., & Putnam, A. J.
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-05-01
- Volume
- 24
- Issue
- 5
- Pages
- 886-898
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2070831457
- Cited by
- 226
- References
- 2
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Khatiwala, C. B., Kim, P. D., Peyton, S. R., & Putnam, A. J. (2009). ECM Compliance Regulates Osteogenesis by Influencing MAPK Signaling Downstream of RhoA and ROCK. Journal of Bone and Mineral Research. https://doi.org/10.1359/jbmr.081240
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