自噬通过LepR+基质细胞调控与年龄相关的颌骨丧失

Journal of dental research Pub Date : 2024-09-01 Epub Date: 2024-08-26 DOI:10.1177/00220345241264810
B Sun, Y Xu, H Wang, F Wang, Q Li, Y Chen, Z Wang
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摘要

骨质老化与颌骨自噬活性降低有关,但在颌骨中的研究却很少。本研究旨在描述衰老的颌骨和颌骨衍生基质细胞(JBSCs)的特征,并确定自噬在颌骨质量下降中的作用。我们观察到,老年人和小鼠的颌骨表现出类似的与年龄相关的骨质流失。此外,瘦素受体(LepR)系细胞是体外培养和扩增 JBSCs(称为 LepR-Cre+/JBSCs)的主要来源。来自颌骨和LepR-Cre+/JBSCs的RNA测序数据显示,在衰老过程中,磷酸肌醇3-激酶(PI3K)/蛋白激酶B(AKT)/哺乳动物雷帕霉素靶标(mTOR)通路的表达上调。通过单细胞转录组学,我们发现在衰老的骨组织中,成骨系细胞比例下降,LepR系细胞的PI3K/AKT通路被激活。老年小鼠(O-mice;O-JBSCs)的颌骨和 LepR-Cre+/JBSCs 中出现了基础自噬活性降低、自噬通量减少和成骨减少的现象。药物和组成型自噬激活缓解了 O-JBSCs 中受损的成骨过程。此外,抑制 mTOR 诱导的自噬也改善了 O-JBSCs 的衰老表型。使用化学自噬激活剂激活 LepR-Cre+/JBSCs 的自噬可减少 O 型小鼠的牙槽骨吸收。因此,我们的研究证明 ATG 分子和通路在颌骨老化中至关重要,为了解与年龄相关的颌骨损失提供了新的方法。
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Autophagy Regulates Age-Related Jawbone Loss via LepR+ Stromal Cells.

Bone aging and decreased autophagic activity are related but poorly explored in the jawbone. This study aimed to characterize the aging jawbones and jawbone-derived stromal cells (JBSCs) and determine the role of autophagy in jawbone mass decline. We observed that the jawbones of older individuals and mice exhibited similar age-related bone loss. Furthermore, leptin receptor (LepR)-lineage cells served as the primary source for in vitro cultured and expanded JBSCs, referred to as LepR-Cre+/JBSCs. RNA-sequencing data from the jawbones and LepR-Cre+/JBSCs showed the upregulated expression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway during aging. Through single-cell transcriptomics, we identified a decrease in the proportion of osteogenic lineage cells and the activation of the PI3K/AKT pathway in LepR-lineage cells in aging bone tissues. Reduced basal autophagic activity, diminished autophagic flux, and decreased osteogenesis occurred in the jawbones and LepR-Cre+/JBSCs from older mice (O-mice; O-JBSCs). Pharmacologic and constitutive autophagy activation alleviated the impaired osteogenesis in O-JBSCs. In addition, the suppression of mTOR-induced autophagy improved the aging phenotype of O-JBSCs. The activation of autophagy in LepR-Cre+/JBSCs using chemical autophagic activators reduced the alveolar bone resorption in O-mice. Therefore, our study demonstrated that ATG molecules and pathways are crucial in jawbone aging, providing novel approaches to understanding age-related jawbone loss.

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