嘌呤能受体P2rx7介导的ATP传感通过指导间充质干细胞的线粒体健康来预防骨骼衰老。
The purinergic receptor P2rx7 mediated ATP sensing is required to prevent bone aging by directing mitochondrial fitness of MSCs.
作者信息
Zhuang Zimeng, Han Chunshan, Cai Meilian, Li Mingzhao, Lin Shuai, Chen Liujing, Zhu Zilu, Zhang Han, Xing Chenyang, Han Bing, Yang Ruili
机构信息
Department of Orthodontics, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, PR China; National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Haidian District, Beijing 100081, PR China; Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Haidian District, Beijing 100081, PR China.
Department of Orthodontics, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, PR China; National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Haidian District, Beijing 100081, PR China; Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Haidian District, Beijing 100081, PR China.
出版信息
J Adv Res. 2025 Jun 13. doi: 10.1016/j.jare.2025.06.026.
BACKGROUND
Bone aging, displays osteoporosis and impaired bone formation, intricately linked to the metabolic alteration of mesenchymal stem cells (MSCs). However, the precise mechanisms underlying this relationship remain unclear.
OBJECTIVES
To determine how P2rx7 modulates mitochondrial dynamics during bone aging and osteogenic differentiation of MSCs.
METHODS
We established P2rx7 mice, to verify the role of P2rx7 in bone metabolism and aging. The bone phenotype was evaluated by micro-CT and histological analyses. The differentiations of MSCs were analyzed by Alizarin red staining and alkaline phosphatase staining. Mitochondrial function was assessed by Seahorse assay, ATP content and membrane potential. Mitochondrial morphology was analyzed by transmission electron microscopy and confocal microscopy.
RESULTS
A decreased expression of P2rx7 concurrent with abnormal mitochondrial dynamics was observed in aged bone tissue. To confirm the role of P2rx7 in bone metabolism and aging, we deleted P2rx7 by using P2rx7 mice and the mice demonstrated premature and exacerbated bone aging. Mechanically, deletion of P2rx7 attenuated the sensitivity of ERK pathway to stimulus, which in turn weakened mitochondrial fusion and resulted in a sparsely connected mitochondrial network via Mitofusion 1. Consistently, P2rx7 deficiency impaired the mitochondrial fitness and bone formation of MSCs. The activation of P2rx7 in MSCs by Benzoylbenzoyl-ATP enhanced the sensitivity of ERK signaling, thereby enhancing mitochondrial fusion and promoting the osteogenic differentiation of MSCs and bone regeneration. Furthermore, restoring mitochondrial fitness in MSCs by Dichloroacetate could rescue the impaired bone regeneration and bone aging observed in P2rx7 mice.
CONCLUSION
Taken together, our results highlight a role for P2rx7 in regulating mitochondrial dynamics coordinates with ERK pathway, thereby highlighting P2rx7 as a promising target to rejuvenate the tissue aging.
背景
骨老化表现为骨质疏松和骨形成受损，与间充质干细胞（MSC）的代谢改变密切相关。然而，这种关系背后的确切机制仍不清楚。
目的
确定P2rx7如何在骨老化和MSC成骨分化过程中调节线粒体动力学。
方法
我们构建了P2rx7基因敲除小鼠，以验证P2rx7在骨代谢和老化中的作用。通过显微CT和组织学分析评估骨表型。通过茜素红染色和碱性磷酸酶染色分析MSC的分化。通过海马实验、ATP含量和膜电位评估线粒体功能。通过透射电子显微镜和共聚焦显微镜分析线粒体形态。
结果
在老年骨组织中观察到P2rx7表达降低，同时伴有线粒体动力学异常。为了证实P2rx7在骨代谢和老化中的作用，我们使用P2rx7基因敲除小鼠删除了P2rx7，这些小鼠表现出过早和加剧的骨老化。机制上，删除P2rx7减弱了ERK通路对刺激的敏感性，进而削弱了线粒体融合，并通过Mitofusion 1导致线粒体网络连接稀疏。一致地，P2rx7缺陷损害了MSC的线粒体适应性和骨形成。通过苯甲酰苯甲酰-ATP激活MSC中的P2rx7增强了ERK信号的敏感性，从而增强了线粒体融合并促进了MSC的成骨分化和骨再生。此外，通过二氯乙酸恢复MSC中的线粒体适应性可以挽救P2rx7基因敲除小鼠中观察到的受损骨再生和骨老化。
结论
综上所述，我们的结果突出了P2rx7在与ERK通路协调调节线粒体动力学中的作用，从而突出了P2rx7作为使组织老化恢复活力的有希望的靶点。
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