Vx-11e protects against titanium-particle-induced osteolysis and osteoclastogenesis by supressing ERK activity
Vx-11e protects against titanium-particle-induced osteolysis and osteoclastogenesis by supressing ERK activity
复制标题
Vx-11e 通过抑制 ERK 活性来防止钛颗粒诱导的骨溶解和破骨细胞生成
DOI：
10.1016/j.bbrc.2019.05.054
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发表时间：
2019-07-05
影响因子：
3.1
通讯作者：
Qin, An
中科院分区：
文献类型：
--
作者：
Li, Chen;Wu, Zuoxing;Qin, An
磨损颗粒引起的假体周围骨溶解是全关节置换术后最常见的长期并发症，常导致假体无菌性松动。破骨细胞在溶骨过程中起关键作用。目前，缺乏临床有效的措施来预防或治疗ped-prosthetic骨溶解，因此，鉴定新的药物，可以抑制骨吸收增强是必要的。通过这项研究，我们发现，特异性和有效的ERK 1/2抑制剂，VX-11 e，可以防止在体内钛（Ti）颗粒引起的颅骨骨质溶解。低剂量VX-11 e轻度降低破骨细胞再吸收，而高剂量VX-11 e治疗未观察到颅骨骨质溶解。组织学检查显示VX-11 e处理组中破骨细胞较少，骨侵蚀减少。体外细胞分析表明，Vx-11 e抑制BMM前体对RANKL的反应形成破骨细胞，以及成熟破骨细胞的骨吸收。机制上，Vx-11 e通过抑制其激酶活性从而阻断下游底物的磷酸化来损害RANKL诱导的ERKI/2信号传导。Vx-11 e还可显著降低RANKL介导的ACP 5/TRAcP、CTR、MMP-9、CISK等基因的表达。总的来说，我们的数据为VX-11 e治疗由极度活跃的破骨细胞生成引起的骨质溶解疾病的潜在治疗用途提供了证据。(C)2019爱思唯尔公司All rights reserved.
Wear particle-induced osteolysis around the prosthesis is the most common long-term complication after total joint replacement surgery which often leads to aseptic loosening of the prosthesis. Osteoclasts play key roles in the osteolytic process. Currently there is a lack of clinically effective measures to prevent or treat ped-prosthetic osteolysis and thus identification of new agents that can inhibit the enhanced osteoclastic bone resorption is warranted. Through this study, we discovered that the specific and potent ERK1/2 inhibitor, Vx-11e, can protect against calvarial osteolysis caused by titanium (Ti) particles in vivo. Low doses of Vx-11e mildly reduced osteoclast resorption whilst no calvarial osteolysis was observed with high dose Vx-11e treatment. Histological examination showed fewer osteoclasts and reduced bone erosion in the Vx-11e treated groups. In vitro cellular analyses showed that Vx-11e inhibited osteoclast formation from BMM precursors in response to RANKL, as well as bone resorption by mature osteoclasts. Mechanistically, Vx-11e impaired RANKL-induced ERKI/2 signaling by inhibiting its kinase activity thereby blocking the phosphorylation of downstream substrates. Moreover, Vx-11e significantly reduced the expression of RANKL-mediated genes such as ACP5/TRAcP, CTR, MMP-9, CISK. Collectively, our data provides evidence for the potential therapeutic use of Vx-11e for the treatment of osteolysis diseases caused by extremely actived osteoclastogenesis. (C) 2019 Elsevier Inc. All rights reserved.