Protein phosphatase 2A as a new target for downregulating osteoclastogenesis and alleviating titanium particle-induced bone resorption. (June 2018)

• Record Type: Journal Article
• Authors: Wang, Liangliang; Guo, Xiaobin; Zhou, Wei; Ding, Yayun; Shi, Jiawei; Wu, Xiexing; Liu, Yu; Xu, Yaozeng; Yang, Huilin; Geng, Dechun
• Is Part Of: Acta biomaterialia. Volume 73(2018)
• Page Start: 488
• Page End: 499
• Publication Date: 2018-06
• Subjects: Protein phosphatase 2A -- Wear particles -- Peri-prosthetic osteolysis -- Osteoclastogenesis -- RANKL; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2018.04.013
• Languages: English
• ISSNs: 1742-7061

Abstract

Graphical abstract: Abstract: Receptor activator of nuclear factor-кB ligand (RANKL)-induced osteoclastogenesis is believed to play a critical role in osteolytic diseases including peri -prosthetic osteolysis (PPO), the primary reason for implant failure and revision surgery. In this study, we observed that protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, was highly expressed in human periprosthetic interface membranes with aseptic loosening and in a murine osteolysis model induced by titanium particle irritation. PP2A inhibition effectively alleviated titanium particle-induced bone destruction at osteolytic sites. In addition, PP2A downregulation significantly decreased osteoclast numbers and RANKL expression, compared with in animals treated with only titanium. Mechanistically, a PP2A selective inhibitor or PP2A siRNA suppressed osteoclastogenesis and alleviated osteoclastic resorption by inhibiting the RANKL-induced nuclear factor-кB and c-Jun N-terminal kinase signaling pathways. Downstream NFATc1 and c-Fos expression were also substantially suppressed by PP2A inhibition or knockdown. Our findings support the importance of PP2A during osteoclastogenesis, identifying PP2A as a novel target for treating particle-induced or other osteoclast-mediated bone resorption diseases. Statement of significance: Excessive osteoclast activation disrupts bone homeostasis and leads to osteoclast-mediated bone resorption diseases, such as peri -prosthetic osteolysis, regarded as the primary reason for implant failure and revision surgery. Here, we firstly demonstrated protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, was highly expressed in human periprosthetic interface membranes with aseptic loosening and murine osteolysis model. Moreover, PP2A inhibition effectively alleviated titanium particle-induced bone destruction and decreased osteoclast numbers. Meanwhile, a PP2A selective inhibitor or PP2A siRNA suppressed osteoclastogenesis and alleviated osteoclastic resorption by inhibiting the nuclear factor-кB and c-Jun N-terminal kinase signaling pathways. Thus, PP2A is involved in osteoclastogenesis and could be a promising target for regulating bone homeostasis and osteolytic responses.