Protein phosphatase 2A as a new target for downregulating osteoclastogenesis and alleviating titanium particle-induced bone resorption.
In: Acta biomaterialia, Jg. 73 (2018-06-01), S. 488
Online
academicJournal
Zugriff:
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.
(Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
Titel: |
Protein phosphatase 2A as a new target for downregulating osteoclastogenesis and alleviating titanium particle-induced bone resorption.
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Autor/in / Beteiligte Person: | Wang, L ; Guo, X ; Zhou, W ; Ding, Y ; Shi, J ; Wu, X ; Liu, Y ; Xu, Y ; Yang, H ; Geng, D |
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Zeitschrift: | Acta biomaterialia, Jg. 73 (2018-06-01), S. 488 |
Veröffentlichung: | Kidlington, Oxford, UK : Elsevier, c2004-, 2018 |
Medientyp: | academicJournal |
ISSN: | 1878-7568 (electronic) |
DOI: | 10.1016/j.actbio.2018.04.013 |
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