Role of PCSK9 in the Development of Mouse Periodontitis Before and After Treatment: A Double-Edged Sword
Role of PCSK9 in the Development of Mouse Periodontitis Before and After Treatment: A Double-Edged Sword
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PCSK9 在治疗前后小鼠牙周炎发展中的作用：一把双刃剑
DOI：
10.1093/infdis/jix574
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发表时间：
2018-02-15
影响因子：
6.4
通讯作者：
Huang, Cui
中科院分区：
文献类型：
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作者：
Sun, Hua Ling;Wu, Yan Ru;Huang, Cui
牙周炎是一种高度流行的感染性疾病，与冠心病（CHD）的遗传相关。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9），冠心病的关键调节剂，对牙周炎的影响尚未研究。在这里，我们发现PCSK 9的表达增加牙周炎患者和牙龈卟啉单胞菌（Pg）感染的小鼠。PCSK 9的缺失减弱了小鼠中Pg诱导的牙周骨丢失。首先，在体外和体内，PCSK 9缺乏减少了炎症相关细胞因子的释放，如肿瘤坏死因子α（TNF-α）和白细胞介素1β。其次，它的缺乏部分通过分别上调CD 36和低密度脂蛋白受体（LDLR）来增强Pg入侵期间的Pg和内毒素清除。然而，黄连素治疗后，PCSK 9基因敲除组的牙周骨再生明显低于野生型。这是因为PCSK 9过表达促进了TNF-α预攻击的牙周膜干细胞（PDLCs）的成骨分化。此外，PCSK 9可通过与TRAF 2相互作用抑制NF-κB信号通路来拯救PDLC成骨。这些结果表明，PCSK 9可能是治疗牙周炎的有效药物靶点。
Periodontitis is a highly prevalent infectious disease associated genetically with coronary heart disease (CHD). The effects of proprotein convertase subtilisin/kexin type 9 (PCSK9), a critical regulator of CHD, on periodontitis have not been studied to date. Here, we found that PCSK9 expression was increased in periodontitis patients and Porphyromonas gingivalis (Pg)-infected mice. Loss of PCSK9 attenuated Pg-induced periodontal bone loss in mice. First, PCSK9 deficiency reduced the release of inflammation-associated cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 1β, in vitro and in vivo. Second, its deficiency enhanced Pg and endotoxin clearance during Pg invasion in part by upregulating CD36 and low-density lipoprotein receptor (LDLR), respectively. However, after berberine treatment, periodontal bone regeneration in the PCSK9 knockout group was significantly lower than that in wild-type. This was because PCSK9 overexpression promoted osteogenic differentiation of periodontal ligament stem cells (PDLCs) prechallenged by TNF-α. Furthermore, PCSK9 could rescue PDLC osteogenesis by repressing the NF-κB signaling pathway by interacting with TRAF2. These results suggest that PCSK9 may be a potent drug target for treating periodontitis.