Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
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DOI：
10.1038/s41598-020-68566-2
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发表时间：
2020-07-15
影响因子：
4.6
通讯作者：
Greaves, Laura C.
中科院分区：
文献类型：
--
作者：
Dobson, Philip F.;Dennis, Ella P.;Greaves, Laura C.
骨矿物质密度下降的发病机制，衰老的普遍特征，还没有完全了解。体细胞线粒体DNA （mtDNA）突变在人体组织中随着年龄的增长而积累，越来越多的证据表明它们可能是衰老过程中不可或缺的一部分。为了探索mtDNA突变对骨生物学的潜在影响，我们比较了衰老系列野生型小鼠和PolgA（mut/mut）线粒体DNA突变小鼠的骨微结构和更替。体内分析显示，两组小鼠都出现了与年龄相关的骨质流失；然而，在PolgA（mut/mut）小鼠中，这一过程明显加快。与野生型小鼠相比，PolgA（mut/mut）小鼠的骨形成率显著降低、成骨细胞种群密度降低、破骨细胞种群密度增加、成骨细胞和破骨细胞线粒体呼吸链缺乏与骨质丢失速度加快有关。体外实验表明，矿化基质形成严重受损，PolgA（mut/mut）细胞的破骨细胞吸收增加。最后，对一组PolgA（mut/mut）小鼠进行运动干预，在体外对骨量或矿化基质形成没有影响。我们的数据表明，线粒体功能障碍是人类衰老的普遍特征，它会损害骨生成，并与骨质流失加速有关。
The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgA(mut/mut) mitochondrial DNA 'mutator' mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgA(mut/mut) mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgA(mut/mut) mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgA(mut/mut) cells. Finally, application of an exercise intervention to a subset of PolgA(mut/mut) mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.