Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA.
Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY, USA.
Bone Res. 2023 Sep 27;11(1):50. doi: 10.1038/s41413-023-00283-8.
Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.
骨骼干细胞和祖细胞 (SSPCs) 执行骨骼维护和修复功能。随着年龄的增长，它们产生的成骨细胞越来越少，脂肪细胞越来越多，导致骨骼完整性丧失。这种有害转化的分子机制在很大程度上尚不清楚。单细胞 RNA 测序显示，Notch 信号在衰老过程中在 SSPCs 中升高。为了研究 Notch 活性增加的作用，我们在体内删除了 SSPC 中的 Nicastrin，这是 Notch 途径的一个必需组成部分。中年条件性敲除小鼠表现出 SSPC 成骨谱系基因表达升高、小梁骨量增加、骨髓脂肪减少和骨修复增强。因此，Notch 调节 SSPC 细胞命运决定，适度调节 Notch 信号可改善骨骼衰老表型，甚至使骨量增加超过年轻小鼠。最后，我们确定转录因子 Ebf3 是 SSPCs 中 Notch 信号的下游介质，它在衰老过程中失调，这突出了它作为一种有前途的治疗靶点，可使衰老骨骼恢复活力。
