Protein phosphatase 2A as a new target for downregulating osteoclastogenesis and alleviating titanium particle-induced bone resorption
Protein phosphatase 2A as a new target for downregulating osteoclastogenesis and alleviating titanium particle-induced bone resorption
复制标题
蛋白磷酸酶2A作为下调破骨细胞生成和减轻钛颗粒诱导的骨吸收的新靶点
DOI：
10.1016/j.actbio.2018.04.013
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发表时间：
2018
影响因子：
9.7
通讯作者：
Geng Dechun
中科院分区：
文献类型：
--
作者：
Wang Liangliang;Guo Xiaobin;Zhou Wei;Ding Yayun;Shi Jiawei;Wu Xiexing;Liu Yu;Xu Yaozeng;Yang Huilin;Geng Dechun
核因子受体激活剂-кB配体(RANKL)诱导的破骨细胞生成在包括假体周围骨溶解在内的溶骨性疾病中起关键作用，而PPO是种植体失败和翻修手术的主要原因。在本研究中，我们观察到一种主要的丝氨酸-苏氨酸磷酸酶PP2A在无菌性松动的人假体周围界膜和钛颗粒刺激诱导的小鼠骨溶解模型中高表达。抑制PP2A能有效减轻钛颗粒引起的溶骨部位的骨破坏。此外，与单纯用钛治疗的动物相比，PP2A下调显著减少了破骨细胞数量和RANKL的表达。在机制上，PP2A选择性抑制剂或PP2A siRNA通过抑制RANKL诱导的核因子-кB和c-Jun氨基末端激酶信号通路来抑制破骨细胞的形成和减轻破骨细胞的吸收。下游NFATc1和c-Fos的表达也被PP2A抑制或敲除。我们的发现支持PP2A在破骨细胞形成过程中的重要性，确认PP2A是治疗颗粒诱导或其他破骨细胞介导性骨吸收疾病的新靶点。意义陈述：过度的破骨细胞激活扰乱了骨的动态平衡，并导致破骨细胞介导性骨吸收疾病，如假体骨溶解，被认为是种植失败和翻修手术的主要原因。在此，我们首先通过无菌性松动和小鼠骨溶解模型，证明了蛋白磷酸酶2A(PP2A)是一种主要的丝氨酸-苏氨酸磷酸酶，在人假体周围界面膜上高表达。此外，抑制PP2A有效地减轻了钛颗粒引起的骨破坏，减少了破骨细胞的数量。同时，PP2A选择性抑制剂或PP2AsiRNA通过抑制核因子-кB和c-jun氨基末端激酶信号通路，抑制破骨细胞的生成，减轻破骨细胞的吸收。因此，PP2A参与了破骨细胞的形成，有望成为调节骨稳态和溶骨反应的靶点。
Receptor activator of nuclear factor-кB ligand (RANKL)-induced osteoclastogenesis is believed to play a critical role in osteolytic diseases includingperi-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 significanceExcessive osteoclast activation disrupts bone homeostasis and leads to osteoclast-mediated bone resorption diseases, such asperi-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.