The age-related characteristics in bone microarchitecture, osteoclast distribution pattern, functional and transcriptomic alterations of BMSCs in mice

IF 5.3 3区医学 Q2 CELL BIOLOGY Mechanisms of Ageing and Development Pub Date : 2023-10-12 DOI:10.1016/j.mad.2023.111877

QianKun Yang , ZhiYuan Wei , XiaoYu Wei , Jie Zhang , Yong Tang , Xiang Zhou , Pan Liu , Ce Dou , Fei Luo

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Abstract

Deteriorated age-related bone loss is the hallmarks of skeletal aging. However, how the aging of bone marrow mesenchymal stem cells (BMSCs) and osteoclasts are linked to the bone microstructure degeneration is not yet very clear. In this study, the characteristics of age-related bone loss, distribution patterns of osteoclasts, functional and transcriptomic alterations of BMSCs, hub genes responsible for BMSCs senescence, were analyzed. Our study revealed an age-related declined trends in trabecular and cortical bones of femur, tibia and lumbar vertebra in mice, which was accompanied by a shift from the trabecular to cortical bones in osteoclasts. Additionally, middle-aged or aged mice exhibited remarkably reduced dynamic bone formation capacities, along with reversed osteogenic-adipogenic differentiation potentials in BMSCs. Finally, transcriptomic analysis indicated that aging-related signaling pathways were significantly activated in BMSCs from aged mice (e.g., cellular senescence, p53 signaling pathway, etc.). Also, weighted correlation network analysis (WGCNA) and venn diagram analysis based on our RNA-Seq data and GSE35956 dataset revealed the critical role of PTPN1 in BMSCs senescence. Targeted inhibition of PTP1B with AAV-Ptpn1-RNAi dramatically postponed age-related bone loss in middle-aged mice. Collectively, our study has uncovered the age-dependent cellular characteristics in BMSCs and osteoclasts underlying progressive bone loss with advancing age.

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小鼠骨髓间充质干细胞的骨微结构、破骨细胞分布模式、功能和转录组改变的年龄相关性特征。

与年龄相关的骨质流失恶化是骨骼衰老的标志。然而，骨髓间充质干细胞（BMSCs）和破骨细胞的衰老与骨微结构退化的关系尚不清楚。在这项研究中，分析了与年龄相关的骨丢失的特征、破骨细胞的分布模式、BMSCs的功能和转录组改变，这些基因是导致BMSCs衰老的枢纽基因。我们的研究揭示了小鼠股骨、胫骨和腰椎的小梁和皮质骨与年龄相关的下降趋势，这伴随着破骨细胞从小梁向皮质骨的转移。此外，中老年小鼠的动态骨形成能力显著降低，BMSC的成骨脂肪分化潜力逆转。最后，转录组学分析表明，衰老小鼠骨髓基质干细胞中衰老相关的信号通路（如细胞衰老、p53信号通路等）被显著激活。此外，基于我们的RNA-Seq数据和GSE35956数据集的加权相关网络分析（WGCNA）和venn图分析揭示了PTPN1在骨髓基质干干细胞衰老中的关键作用。AAV-Ptpn1-RNAi对PTP1B的靶向抑制显著延缓了中年小鼠与年龄相关的骨丢失。总之，我们的研究揭示了BMSC和破骨细胞的年龄依赖性细胞特征，这些特征是随着年龄的增长而进行性骨丢失的基础。

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来源期刊

Mechanisms of Ageing and Development 医学-老年医学

CiteScore

11.10

自引率

1.90%

发文量

审稿时长

32 days

期刊介绍： Mechanisms of Ageing and Development is a multidisciplinary journal aimed at revealing the molecular, biochemical and biological mechanisms that underlie the processes of aging and development in various species as well as of age-associated diseases. Emphasis is placed on investigations that delineate the contribution of macromolecular damage and cytotoxicity, genetic programs, epigenetics and genetic instability, mitochondrial function, alterations of metabolism and innovative anti-aging approaches. For all of the mentioned studies it is necessary to address the underlying mechanisms. Mechanisms of Ageing and Development publishes original research, review and mini-review articles. The journal also publishes Special Issues that focus on emerging research areas. Special issues may include all types of articles following peered review. Proposals should be sent directly to the Editor-in-Chief.