Inhibition of protein phosphatase 2A attenuates titanium-particle induced suppression of bone formation

Peri-prosthetic osteolysis (PPO) often generates after total joint arthroplasty, which can bring implant failure and following revision surgery. Wear debris shed from prostheses strongly enhances bone resorption and attenuates bone formation in osteolytic process. We previously proved that suppression of protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, inhibited wear-debris-induced osteoclastogenesis and alleviated local osteolysis. Whether PP2A inhibition facilitates osteoblastogenesis and bone formation in the osteolytic sites remains unclear. Here, we observed that PP2A inhibition with a selective inhibitor attenuated particle-induced bone destruction by accelerating osteoblast differentiation and promoting bone regeneration. Meanwhile, we proved inhibition of PP2A alleviated the inhibition of osteogenic differentiation by titanium particles in MC3T3-E1 cells. In addition, PP2A inhibition increased β-catenin expression and enhanced β-catenin nuclear translocation, compared with that in the vehicle group. ICG-001, a specific inhibitor of β-catenin, was further applied and was found to weaken the effect of PP2A inhibition on β-catenin expression and nuclear translocation. Therefore, we demonstrated PP2A inhibition exerts protective effects on osteogenic differentiation mainly by activating Wnt/β-catenin signaling pathway. Thus, all the results further revealed PP2A could be a promising target for treating PPO and other bone related diseases.