The Study Of Therapeutic Effect On Periprosthetic Osteolysis And Mechanism By Regulation Of Protein Phosphatase 2A

Objective: Protein phosphatase 2A(PP2A),a major serine-threonine phosphatase,has been known to regulate vast phosphatase activity and exert multifunctional influence on oncogenesis,embryonic development,neuropathologies and bone formation.But the relationship between PP2 A and osteoclastogenesis was rarely understood.Therefore,we performed experiments in the study to clarify the connection between PP2 A and osteoclastogenesis and propose a promising target for peri-prosthetic osteolysis and other osteoclast-mediated bone resorption diseases.Methods: PP2 A expression was studied in human joint synovium samples from primary arthroplasty or prosthesis revision for periprosthetic osteolysis(PPO).6-week-old male C57BL/6 mice were implanted titanium particles over the calvaria of and was injected with okadaic acid(OA,4 ?g/kg/day or 0.4 ?g/kg/day)once per day into the periosteum for 2 weeks.Micro-computed tomography and histological study were performed.Effects of PP2 A knockdown with si RNA on osteoclastogensis and osteoclastic bone resorption were investigated using RAW264.7 cell cultures.Mechanisms of PP2 A involved in osteoclastogensis were studied with western blot analysis.Results: PP2 A was highly expressed in human periprosthetic interface membranes with aseptic loosening and in a murine osteolysis model.PP2 A inhibition effectively alleviated titanium particle-induced bone destruction and decreased osteoclast numbers.Mechanistically,PP2 A si RNA suppressed osteoclastogenesis and alleviated osteoclastic bone resorption by inhibiting the receptor activator for nuclear factor-? B ligand(RANKL)-induced nuclear factor-?B(NF-?B)and c-Jun N-terminal kinase(JNK)signaling pathways.Downstream nuclear factor of activated T-cells 1(NFATc1)and c-Fos expression were also suppressed by PP2 A knockdown.Conclusions: Our findings support the importance of PP2 A during osteoclastogenesis,identifying PP2 A as a novel target for treating particle-induced or other osteoclast-mediated bone resorption diseases.