Abstract
We have previously reported that a synthetic mechano-growth factor (MGF) C-terminal E-domain with 25 amino acids (MGF-C25E) promotes rat tenocyte migration through the FAK-ERK1/2 signaling pathway. However, the role of the nucleus in MGF-C25E-promoted tenocyte migration and the molecular mechanisms involved remain unclear. In this study, we demonstrate that MGF-C25E increases the Young’s modulus of tenocytes through the FAK-ERK1/2 signaling pathway. This increase is not accompanied by an obvious change in the expression of Lamin A/C but is accompanied by significant chromatin condensation, indicating that MGF-C25E-induced chromatin condensation may contribute to the increased nuclear stiffness. Moreover, DNA methylation is observed in MGF-C25E-treated tenocytes. Inhibition of DNA methylation suppresses the elevation in chromatin condensation, in nuclear stiffness, and in tenocyte migration induced by MGF-C25E. The inhibition of the focal adhesion kinase (FAK) or extracellular signal regulated kinase 1/2 (ERK1/2) signals represses MGF-C25E-promoted DNA methylation. It also abolishes chromatin condensation, nuclear stiffness, and cell migration. Taken together, our results suggest that MGF-C25E promotes tenocyte migration by increasing nuclear stiffness via the FAK-ERK1/2 signaling pathway. This provides strong evidence for the role of nuclear mechanics in tenocyte migration and new insight into the molecular mechanisms of MGF-promoted tenocyte migration.
Highlights
A tendon is a tough band of fibrous connective tissue that connects muscle to bone
The inhibition of the focal adhesion kinase (FAK) or extracellular signal regulated kinase 1/2 (ERK1/2) signal suppressed the Mechano-growth factor (MGF)-C25E-induced increase in the Young’s modulus (Fig. 2). These results demonstrate that MGF-C25E increases the stiffness of tenocyte nuclei via the FAK-ERK1/2 signaling pathway
We report that MGF-C25E promotes tenocyte migration by inducing DNA methylation and by increasing chromatin condensation and nuclear stiffness via the FAK-ERK1/2 signaling pathway
Summary
A tendon is a tough band of fibrous connective tissue that connects muscle to bone This allows the transmission of forces generated by muscle to bone, which results in joint movement. Previous studies demonstrated that MGF promotes bone-defect healing and induces more blood vessels in bone regeneration around the defective areas[6,10]. It remains unclear whether MGF has the potential to accelerate tendon repair. The important role of cell movement in multiple biological processes such as embryonic development, immune response, wound healing and tissue renewal makes it one of the most fundamental cellular activities. Cell migration is associated with cytoskeleton-mediated relocation of the nucleus within the cells, and an increase in nuclear stiffness can enhance the ability of cytoskeletal elements to relocate the nucleus inside the cell[16]
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