Autophagy negative-regulating Wnt signaling enhanced inflammatory osteoclastogenesis from Pre-OCs in vitro
Autophagy negative-regulating Wnt signaling enhanced inflammatory osteoclastogenesis from Pre-OCs in vitro
复制标题
自噬负调节 Wnt 信号增强体外 Pre-OC 的炎症破骨细胞生成
DOI：
10.1016/j.biopha.2020.110093
复制
发表时间：
2020-06-01
影响因子：
7.5
通讯作者：
Sun, Weilian
中科院分区：
文献类型：
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作者：
Chen, Lili;Yang, Yuting;Sun, Weilian
牙周炎由此引起的牙槽骨的炎症性丢失，是一种在世界范围内广泛存在的现象。这是全世界临床医生面临的一个持续挑战。本研究旨在观察脂多糖（LPS）对体外培养的破骨细胞（OCs）分化的影响，并探讨其分子机制。对于骨髓源性巨噬细胞（被认为是前OC），LPS以剂量依赖性方式损害其向OC的分化。相比之下，它在体外促进Pre-OCs（指核因子-kappa B配体受体激活剂（RANKL）预处理的Pro-OCs）分化为最大直径、数量、覆盖面积和融合指数增加的OCs。促进OCs增殖、骨吸收及OCs相关基因表达。LPS通过激活自噬途径促进前OCs向OCs分化，从而增加OCs特异性基因TRAP、Cts K和NFATC 1的表达。Wnt信号通路成员在LPS诱导的OC形成过程中表达较低，但在自噬抑制剂的存在下可以被拯救。最有希望的观察是LC 3B和Dvl 2的直接相互作用，表明在OC中存在上述途径之间的串扰。综上所述，我们认为LPS激活自噬，其通过Dvl 2的自噬降解负性调节Wnt信号传导，对于体外从Pre-OC的破骨细胞生成是重要的。我们的研究揭示了这样一个事实，即自噬抑制剂将成为一种新的，潜在的适用于治疗牙周骨丢失的治疗选择。
Periodontitis thereby the alveolar bone loss induced by inflammation, is a wide-spread phenomenon around the world. It is an ongoing challenge faced by clinicians worldwide. This study aimed to identify the effects of lipopolysaccharide (LPS) on osteoclasts (OCs) differentiation in vitro and to investigate its molecular mechanism. For bone marrow derived macrophages (considered as Pro-OCs), LPS impaired their differentiation into OCs in a dose-dependent manner. In contrast, it promoted Pre-OCs (referred to receptor activator of nuclear factor-kappa B ligand (RANKL) pretreated Pro-OCs) and differentiated to OCs with increased maximum diameter, quantity, the covering area and the fusion index in vitro. It also facilitated OCs proliferation, bone resorption and OCs related genes expression. Furthermore, it was revealed that LPS enhanced OCs genesis from Pre-OCs via activating autophagy pathway consequently elevated the accumulation of TRAP, Cts K and NFATC1, specific genes of OCs. The members of Wnt signaling were expressed as at lower states during the LPS induced OCs formation, but they could be rescued in the presence of autophagy inhibitor. The most promising observation was the direct interaction of LC3B and Dvl2, indicating that the crosstalk between above pathways existed in OCs. Taken together, we consider that LPS activates autophagy which negatively regulates Wnt signaling via autophagic degradation of Dvl2 is significant for osteoclastogenesis from Pre-OCs in vitro. Our study sheds light on the fact that autophagy inhibitors will become a new, potentially applicable therapeutic option in the treatment of periodontal bone loss.