Osteogenic response of mesenchymal stem cells to continuous mechanical strain is dependent on ERK1/2-Runx2 signaling

Abstract

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.

Effects of Negative Pressure Wound Therapy on Mesenchymal Stem Cells Proliferation and Osteogenic Differentiation in a Fibrin Matrix

“…Our data showed that production of Cbfa1/Runx2 initially increased but then decreased in response to a long period of NPWT treatment. This result was consistent with the report from Huang and Rei [17], and opposite to the reports about osteogenic response of MSCs to continuous mechanical strain [16], [34]. We hypothesize that both mechanical stretch and hydrostatic pressure contribute to the osteoblastic differentiation of P-MSCs, and the cells in fibrin matrix were more sensitive to fluid-shear stress, which may play a leading role in the mechanical stimuli created by NPWT.…”

Biomechanical forces in the skeleton and their relevance to bone metastasis: Biology and engineering considerations

“…Typical 2-D substrates include tissue culture polystyrene [21], glass [145], silicone membrane [146], bone slices [147], and these substrates can also be surface-coated (e.g. with collagen, fibronectin) to study the integrated effects of cell adhesion and loading on mechanotransduction [148].…”

“…the Flexcell® line), and their application has revealed that stretching significantly changes cell behavior. For example, mechanical stretching induces osteogenic differentiation, as detected via increased expression of ALP [146, 152], Runx2 [146, 148, 152, 153], and collagen [146, 148, 153], as well as elevated calcium deposition [154, 155], even in the absence of osteogenic growth factors [156, 157]. As with physiological mechanical loading, this response is enhanced with increasing strain magnitude [153, 157].…”

Mechanical stretch and chronotherapeutic techniques for progenitor cell transplantation and biomaterials

“…The authors also found that this long term application of strain reduced the proliferative capacity of MSCs, supporting the notion that although short-term strains may increase proliferation, long-term strains do not appear to [7]. It has also been shown that both osteoblastogenesis and osteoclastogenesis are influenced by mechanical stimulation, showing how far reaching the effects of mechanical load are in bone formation and maintenance [30, 31]. …”

“…There are many signalling pathways that have been implicated regarding how mechanical stimulation effects osteogenesis, for example, one study shows that the onset of osteogenic differentiation following mechanical stimulation may be dependent on ERK1/2-Runx2 signalling [30]. Another study investigating human BM-MSCs following stretch, reports an induction of FosB, a member of the AP-1 family of transcription factors which regulate osteogenic differentiation and bone formation, in a time-and stretch-dependent manner [32].…”