Tensile force inhibits the proliferation of human periodontal ligament fibroblasts through Ras-p38 MAPK up-regulation

The capacity of human periodontal ligament fibroblasts (PLF) to proliferate in response to mechanical force plays a critical role in orthodontic tooth movement. Extensive research has not fully revealed the mechanisms by which the PLF respond to mechanical force. The responses to force differ according to the origin of cells and the type of stress applied. In this study, we examined the proliferative response of PLF to tensile force. We also explored cellular mechanisms involved in the mechanosignal transduction of tensile force. Application to the force to PLF with 1.5% elongation for 1h inhibited cell proliferation. This was accompanied by reductions in several cyclins and cyclin-dependent kinases (CDKs) involved in the G ₁/S transition; however, p21 knockdown prevented these events. Pharmacological inhibitor of p38 MAPK suppressed the force-mediated growth inhibition as well as the decrease in p21 expression. Ras inhibitor almost completely blocked the tension-mediated increases in p-p38 MAPK and p-p21, and the attendant increase in PLF proliferation. These findings suggest that tension force activates Ras-p38 MAPK pathways in PLF, which up-regulate p21 and arrest cell cycle progression at the G ₁ phase.