PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：全球过度食用单糖对骨骼健康的影响，在青春期/成年早期达到高峰，并与骨质疏松症（OP）和骨折风险相关数十年，不清楚。间充质基质/干细胞(MSCs)是成骨细胞/骨形成细胞的祖细胞,并且已知随着年龄的增长它们的成骨分化能力降低。令人震惊的是,虽然有相关证据表明，消耗最多单糖的青少年骨量最低，对这种相关性的因果关系没有机械理解。
方法：使用人细胞信息对MSC分化过程中涉及的能量通路进行生物信息学分析。使用多源非衰老的人和鼠MSCs评估了正常与高葡萄糖（HG）条件对骨/脂肪谱系定型和线粒体功能的体外解剖；用于体内验证，用正常或添加HG的水喂养幼鼠,随后分析骨髓CD45-MSC。
结果：生物信息学分析显示，线粒体和葡萄糖相关的代谢途径是MSC骨/脂肪谱系确定的组成部分。功能上,由于烟酰胺腺嘌呤二核苷酸(NAD+)的消耗,单独的体外HG降低了MSC线粒体活性和骨生成,同时增强了8小时的脂肪形成,Sirtuin（SIRT）1的重要线粒体辅酶和辅因子，Sirtuin是一种也参与成骨的长寿基因。在体内,年轻小鼠中HG的摄入量耗尽MSCNAD+，口服NAD前体补充剂在1〜5天内以SIRT1依赖性方式迅速逆转线粒体下降和骨/脂肪承诺。
结论：我们发现了过量葡萄糖的惊人快速影响，单一的饮食因素，在年轻环境中MSCSIRT1功能和成骨，以及NAD+-单分子对MSC线粒体功能和谱系承诺的关键作用。鉴于当前全球单糖的过度消费，这些发现对未来的全球OP和残疾风险具有重要意义。
方法：使用人细胞信息对MSC分化过程中涉及的能量通路进行生物信息学分析。使用多源非衰老的人和鼠MSCs评估了正常与高葡萄糖（HG）条件对骨/脂肪谱系定型和线粒体功能的体外解剖；用于体内验证，用正常或添加HG的水喂养幼鼠,随后分析骨髓CD45-MSC。
结果：生物信息学分析显示，线粒体和葡萄糖相关的代谢途径是MSC骨/脂肪谱系确定的组成部分。功能上,由于烟酰胺腺嘌呤二核苷酸(NAD+)的消耗,单独的体外HG降低了MSC线粒体活性和骨生成,同时增强了8小时的脂肪形成,Sirtuin（SIRT）1的重要线粒体辅酶和辅因子，Sirtuin是一种也参与成骨的长寿基因。在体内,年轻小鼠中HG的摄入量耗尽MSCNAD+，口服NAD前体补充剂在1〜5天内以SIRT1依赖性方式迅速逆转线粒体下降和骨/脂肪承诺。
结论：我们发现了过量葡萄糖的惊人快速影响，单一的饮食因素，在年轻环境中MSCSIRT1功能和成骨，以及NAD+-单分子对MSC线粒体功能和谱系承诺的关键作用。鉴于当前全球单糖的过度消费，这些发现对未来的全球OP和残疾风险具有重要意义。
