Role of Pink1 in Regulating Osteoclast Differentiation during Periodontitis.

H Gou, T Wang, Y Chen, Y Zhou, J Li, Y Xu
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Abstract

Periodontitis has recently been recognized as an inflammatory disease caused by oxidative stress, with mitochondrial dysfunction being a key factor leading to oxidative stress. PTEN-induced kinase 1 (PINK1) is an essential protein for mitochondrial quality control, which protects cells from oxidative stress by inducing mitophagy to degrade damaged mitochondria, but its role in periodontitis has not been elucidated. This study aimed to explore the contribution and underlying mechanisms of Pink1 in regulating the differentiation and function of osteoclasts during periodontitis. Here we observed a significant downregulation of PINK1 expression in periodontitis-affected tissues. Then we constructed a periodontitis model in mice with fluorescently labeled mononuclear/macrophages, and the results showed that as the modeling time extended, the alveolar bone destruction gradually worsened and was accompanied by gradually decreased Pink1 expression in osteoclasts and a significantly increased osteoclast number. In vitro experiments further demonstrated a negative correlation between Pink1 and osteoclast differentiation. In addition, alveolar bone destruction in the Pink1 knockout mice was significantly more advanced than that in the littermate wild type mice after ligature-induced periodontitis and enhanced osteoclastogenesis and bone-resorptive capacity in vitro. RNA-sequencing analysis and in vitro validation revealed that the absence of Pink1 led to a decrease in oxidative phosphorylation levels and an enhancement of calcium-mediated signaling, specifically the calcineurin-NFATc1 pathway, via an intracellular calcium source. Further mechanistic studies found that the deficiency of Pink1 inhibited mitophagy but strengthened mitochondrial-endoplasmic reticulum coupling, which, by promoting the interaction of Mfn2-IP3R-VDAC1 proteins, increased the concentration of mitochondrial calcium ions, thereby triggering more active osteoclast differentiation. The aforementioned process can be reversed by the IP3R channel inhibitor Bcl-XL. These findings unveiled that Pink1 was involved in osteoclast differentiation by regulating mitochondrial calcium transport mediated by mitochondria-associated endoplasmic reticulum membranes, providing a new theoretical basis for the pathogenesis and treatment of periodontitis.

Pink1在牙周炎中调节破骨细胞分化中的作用。
牙周炎最近被认为是氧化应激引起的炎症性疾病,线粒体功能障碍是导致氧化应激的关键因素。pten诱导的激酶1 (PINK1)是线粒体质量控制的必需蛋白,通过诱导线粒体自噬降解受损的线粒体来保护细胞免受氧化应激,但其在牙周炎中的作用尚未阐明。本研究旨在探讨Pink1在牙周炎中调节破骨细胞分化和功能的作用及其机制。我们观察到,在牙周炎影响的组织中,PINK1的表达显著下调。然后用荧光标记的单核/巨噬细胞构建小鼠牙周炎模型,结果显示,随着造模时间的延长,牙槽骨破坏逐渐加重,破骨细胞中Pink1表达逐渐降低,破骨细胞数量明显增加。体外实验进一步证实了Pink1与破骨细胞分化呈负相关。此外,在结扎诱导的牙周炎后,Pink1基因敲除小鼠的牙槽骨破坏明显比同龄野生型小鼠更早,体外破骨细胞生成和骨吸收能力增强。rna测序分析和体外验证表明,Pink1的缺失导致氧化磷酸化水平降低,钙介导的信号通路增强,特别是钙调磷酸酶- nfatc1通路,通过细胞内钙源。进一步的机制研究发现,Pink1缺乏抑制了线粒体自噬,但增强了线粒体-内质网偶联,这种偶联通过促进Mfn2-IP3R-VDAC1蛋白的相互作用,增加了线粒体钙离子浓度,从而引发更活跃的破骨细胞分化。上述过程可被IP3R通道抑制剂Bcl-XL逆转。这些发现揭示了Pink1通过调节线粒体相关内质网膜介导的线粒体钙转运参与破骨细胞分化,为牙周炎的发病和治疗提供了新的理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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