Autophagy inhibitors 3-MA and LY294002 repress osteoclastogenesis and titanium particle-stimulated osteolysis
Autophagy inhibitors 3-MA and LY294002 repress osteoclastogenesis and titanium particle-stimulated osteolysis
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自噬抑制剂 3-MA 和 LY294002 抑制破骨细胞生成和钛颗粒刺激的骨溶解
DOI：
10.1039/d1bm00691f
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发表时间：
2021-05-25
影响因子：
6.6
通讯作者：
Sheng, Puyi
中科院分区：
文献类型：
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作者：
Chen, Weishen;Xian, Guoyan;Sheng, Puyi
假体周围骨溶解（PIO）引起的无菌性松动是关节置换术后常见的并发症，目前仍没有比翻修手术更好的治疗方法。磨损颗粒引起的炎症反应，特别是随后的破骨细胞骨吸收，是造成PIO的原因。由于磨损颗粒在诱导PIO假体周围细胞自噬中的重要性已被发现，这可能是无菌性松动的核心过程。然而，磨损颗粒诱导的自噬在PIO期间破骨细胞发生中的作用尚不清楚。在本研究中，我们研究了自噬在破骨细胞发生中的作用，并在小鼠颅骨骨溶解模型中进行了验证。我们发现无菌性松动患者的界面膜中破骨细胞增加。体外实验发现，敲除Atg5基因或使用自噬抑制剂（3-MA、LY294002）抑制自噬可抑制破骨细胞的发生，降低破骨细胞相关基因TRAP、组织蛋白酶K和基质金属蛋白9 （MMP-9）的表达。在体内，3-MA和LY294002抑制钛颗粒刺激的骨溶解和破骨细胞生成，降低促炎因子tnf - α、IL-1 β和IL-6的表达。提示3-MA和LY294002可能是预防和治疗PIO和无菌性松动的潜在药物。
Aseptic loosening caused by peri-implant osteolysis (PIO) is a common complication after joint replacement, and there is still no better treatment than revision surgery. The wear particle-induced inflammation response, especially subsequent osteoclastic bone resorption, is responsible for PIO. As the importance of wear particles in inducing autophagy in cells around the prosthesis in PIO has been discovered, this might be a central process underlying aseptic loosening. However, the role of autophagy induced by wear particles in osteoclastogenesis during PIO remains unclear. In this study, we investigated the role of autophagy in osteoclastogenesis and verified it in a mouse calvarial osteolysis model. We found that osteoclasts were increased in the interface membranes of patients with aseptic loosening. In vitro, knocking down the Atg5 gene or using autophagy inhibitors (3-MA, LY294002) to inhibit autophagy was found to repress osteoclastogenesis and decrease expression of the osteoclast-related genes TRAP, cathepsin K, and matrix metalloprotein 9 (MMP-9) with or without titanium (Ti) particles. In vivo, 3-MA and LY294002 repressed Ti particle-stimulated osteolysis and osteoclastogenesis and reduced expression of the pro-inflammatory factors TNF-alpha, IL-1 beta, and IL-6. Our results suggest that 3-MA and LY294002 might be the potential medicines to prevent and treat PIO and aseptic loosening.