Department of Orthopedics, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education, Shanghai, China.
Front Endocrinol (Lausanne). 2022 Jun 30;13:922501. doi: 10.3389/fendo.2022.922501. eCollection 2022.
Senile osteoporosis is a chronic skeletal disease, leading to increased bone brittleness and risk of fragile fractures. With the acceleration of population aging, osteoporosis has gradually become one of the most serious and prevalent problems worldwide. Bone formation is highly dependent on the proper osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in the bone marrow microenvironment, which is generated by the functional relationship among different cell types, including osteoblasts, adipogenic cells, and bone marrow stromal cells in the bone marrow. It is still not clear how osteoporosis is caused by its molecular mechanism. With aging, bone marrow is able to restrain osteogenesis. Discovering the underlying signals that oppose BMSC osteogenic differentiation from the bone marrow microenvironment and identifying the unusual changes in BMSCs with aging is important to elucidate possible mechanisms of senile osteoporosis. We used 3 gene expression profiles (GSE35956, GSE35957, and GSE35959) associated with osteoporosis. And a protein-protein interaction (PPI) network was also built to identify the promising gene CD137. After that, we performed experiments to verify its function and mechanism. In this experiment, we found that significant bone loss was observed in aged (18-month-old) mice compared with young (6-month-old) mice. The adipose tissue in bone marrow cavity from aged mice reached above 10 times more than young mice. Combining bioinformatics analysis and vivo experiments, we inferred that CD137 might be involved in the p53 and canonical Wnt/β-catenin signaling pathways and thereby influenced bone mass through regulation of marrow adipogenesis. Importantly, osteoporosis can be rescued by blocking CD137 signaling . Our research will contribute to our understanding not only of the pathogenesis of age-related bone loss but also to the identification of new targets for treating senile osteoporosis.
老年性骨质疏松症是一种慢性骨骼疾病，会导致骨骼脆性增加，骨折风险增加。随着人口老龄化的加速，骨质疏松症已逐渐成为全球最严重和普遍的问题之一。骨骼的形成高度依赖于骨髓间充质干细胞（BMSCs）在骨髓微环境中的适当成骨分化，这是由不同细胞类型之间的功能关系产生的，包括成骨细胞、脂肪细胞和骨髓基质细胞。其分子机制尚不清楚。随着年龄的增长，骨髓能够抑制成骨作用。从骨髓微环境中发现对抗 BMSC 成骨分化的潜在信号，并识别衰老时 BMSCs 的异常变化，对于阐明老年性骨质疏松症的可能机制非常重要。我们使用了 3 个与骨质疏松症相关的基因表达谱（GSE35956、GSE35957 和 GSE35959）。并构建了蛋白质-蛋白质相互作用（PPI）网络来识别有前途的基因 CD137。之后，我们进行了实验来验证其功能和机制。在这个实验中，我们发现与年轻（6 月龄）小鼠相比，老年（18 月龄）小鼠的骨量明显减少。老年小鼠骨髓腔中的脂肪组织比年轻小鼠多 10 倍以上。通过生物信息学分析和体内实验相结合，我们推断 CD137 可能参与 p53 和经典 Wnt/β-catenin 信号通路，并通过调节骨髓脂肪生成来影响骨量。重要的是，阻断 CD137 信号可以挽救骨质疏松症。我们的研究不仅有助于我们理解与年龄相关的骨丢失的发病机制，而且有助于确定治疗老年性骨质疏松症的新靶点。
