Osteogenic response of mesenchymal stem cells to continuous mechanical strain is dependent on ERK1/2-Runx2 signaling.
ABSTRACT Mechanical stimuli are responsible for bone remodeling during orthodontic tooth movement. The role of mechanical stimulation in the regulation of the fate of bone mesenchymal stem cells (BMSCs) is of interest in bone regeneration and tissue engineering applications. However, the signaling pathway involved in strain-induced biochemical events in BMSCs is not well established and can be controversial. This study investigated strain-induced proliferation and differentiation of BMSCs, as well as the mechanism of mechanotransduction. BMSCs were exposed to continuous mechanical strain (CMS) of 10% at 1 Hz. The results showed that CMS reduced the proliferation of BMSCs and stimulated osteogenic differentiation by activating Runx2, followed by increased alkaline phosphatase (ALP) activity and mRNA expression of osteogenesis-related genes (ALP, collagen type I and osteocalcin). Furthermore, the phosphorylation level of extracellular regulated protein kinase (ERK)1/2 increased significantly at the onset of strain. However, the presence of U0126, a selective inhibitor of ERK1/2, blocked the induction of Runx2 and subsequent osteogenic events. These findings demonstrate that CMS regulated Runx2 activation and favored osteoblast differentiation through activation of the ERK1/2 signaling pathway. These results will contribute to a better understanding of strain-induced bone remodeling and will form the basis for the correct choice of applied force in orthodontic treatment.
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ABSTRACT: Mechanical stimulation can influence differentiation pathways of stem cells, and may therefore provide improved control of lineage specifications for clinical applications. Oscillatory mechanical stimulation at relatively low frequencies (0.01 Hz) has recently been shown to suppress adipogenic differentiation of mesenchymal stem cells, indicating that the range of effective stimulation frequencies is not limited to those associated with locomotion, circulation, and respiration. We hypothesized that relatively low frequency mechanical stimulation (0.01 Hz) can also promote osteogenic cell differentiation of myoblastic C2C12 cells in combination with BMP-2. Results indicate that low frequency mechanical stimulation can significantly enhance osteogenic gene expression, provided that differentiation is initiated by a priming period involving BMP-2 alone. Subsequent application of low frequency mechanical stimulation appears to act synergistically with continued BMP-2 exposure to promote osteogenic differentiation of C2C12 cells, and can even partially compensate for the removal of BMP-2. These effects may be mediated by the ERK and Wnt signalling pathways. Osteogenic induction of C2C12 cells by low frequency mechanical stimulation is therefore critically dependent upon previous exposure to growth factors, and the timing of superimposed BMP-2 and mechanical stimuli can sensitively influence osteogenesis. These insights may provide a technically simple means for control of stem cell differentiation in cell-based therapies, particularly for enhancement of differentiation toward desired lineages.ISRN Stem Cells. 01/2013;