Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), No.35, Keyan Road, Zhunan, 35053, Taiwan.
Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, No.1, Section 1, Jen-Ai Road, Taipei, 10051, Taiwan.
J Biomed Sci. 2024 May 13;31(1):49. doi: 10.1186/s12929-024-01039-0.
The impact of global overconsumption of simple sugars on bone health, which peaks in adolescence/early adulthood and correlates with osteoporosis (OP) and fracture risk decades, is unclear. Mesenchymal stromal/stem cells (MSCs) are the progenitors of osteoblasts/bone-forming cells, and known to decrease their osteogenic differentiation capacity with age. Alarmingly, while there is correlative evidence that adolescents consuming greatest amounts of simple sugars have the lowest bone mass, there is no mechanistic understanding on the causality of this correlation.
Bioinformatics analyses for energetics pathways involved during MSC differentiation using human cell information was performed. In vitro dissection of normal versus high glucose (HG) conditions on osteo-/adipo-lineage commitment and mitochondrial function was assessed using multi-sources of non-senescent human and murine MSCs; for in vivo validation, young mice was fed normal or HG-added water with subsequent analyses of bone marrow CD45 MSCs.
Bioinformatics analyses revealed mitochondrial and glucose-related metabolic pathways as integral to MSC osteo-/adipo-lineage commitment. Functionally, in vitro HG alone without differentiation induction decreased both MSC mitochondrial activity and osteogenesis while enhancing adipogenesis by 8 h' time due to depletion of nicotinamide adenine dinucleotide (NAD), a vital mitochondrial co-enzyme and co-factor to Sirtuin (SIRT) 1, a longevity gene also involved in osteogenesis. In vivo, HG intake in young mice depleted MSC NAD, with oral NAD precursor supplementation rapidly reversing both mitochondrial decline and osteo-/adipo-commitment in a SIRT1-dependent fashion within 1 ~ 5 days.
We found a surprisingly rapid impact of excessive glucose, a single dietary factor, on MSC SIRT1 function and osteogenesis in youthful settings, and the crucial role of NAD-a single molecule-on both MSC mitochondrial function and lineage commitment. These findings have strong implications on future global OP and disability risks in light of current worldwide overconsumption of simple sugars.
全球过度消耗简单糖对骨骼健康的影响尚不清楚，骨骼健康在青少年/成年早期达到峰值，与骨质疏松症（OP）和骨折风险相关数十年。间充质基质/干细胞（MSCs）是成骨细胞/骨形成细胞的祖细胞，已知其成骨分化能力随年龄增长而降低。令人震惊的是，虽然有相关性证据表明摄入最多简单糖的青少年骨量最低，但对这种相关性的因果关系还没有机制上的理解。
使用人类细胞信息对 MSC 分化过程中涉及的能量途径进行生物信息学分析。使用多种非衰老人类和鼠 MSC 体外分析正常与高葡萄糖（HG）条件对成骨/脂肪谱系的承诺和线粒体功能；为了进行体内验证，给年轻小鼠喂食正常或添加 HG 的水，然后分析骨髓 CD45 MSC。
生物信息学分析显示，线粒体和葡萄糖相关代谢途径是 MSC 成骨/脂肪谱系承诺的重要组成部分。功能上，HG 单独存在而不诱导分化在 8 小时内降低了 MSC 线粒体活性和成骨作用，同时由于烟酰胺腺嘌呤二核苷酸（NAD）的消耗增强了脂肪生成，NAD 是一种重要的线粒体辅酶和 Sirtuin（SIRT）1 的辅助因子，SIRT1 也是一种与成骨作用相关的长寿基因。在体内，年轻小鼠摄入 HG 会耗尽 MSC 的 NAD，口服 NAD 前体补充剂可在 1~5 天内以 SIRT1 依赖的方式迅速逆转线粒体下降和成骨/成脂分化。
我们发现，在年轻状态下，过量的葡萄糖，即单一饮食因素，对 MSC SIRT1 功能和成骨作用有惊人的快速影响，而 NAD 这单一分子对 MSC 线粒体功能和谱系承诺都有至关重要的作用。鉴于目前全球简单糖的过度消耗，这些发现对未来全球 OP 和残疾风险具有重要意义。
