Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands.
Stem Cells. 2010 May;28(5):916-27. doi: 10.1002/stem.405.
Bone-marrow adipogenesis is an aging-related phenomenon and is correlated with osteoporosis. The latter is a prevalent bone disease in the elderly leading to increased fracture risk and mortality. It is widely hypothesized that the underlying molecular mechanism includes a shift in the commitment of mesenchymal stem cells (MSCs) from the osteogenic lineage to the adipogenic lineage. Lineage skewing is at least partially a result of transcriptional changes. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been proposed as a major decision factor in MSC lineage commitment, promoting adipogenesis at the expense of osteogenesis. Here we found that PPAR-gamma acted unexpectedly to stimulate osteoblast differentiation from human bone marrow-derived MSCs. Both rosiglitazone-mediated activation and overexpression of PPAR-gamma caused acceleration of osteoblast differentiation. Conversely, shRNAi-mediated PPAR-gamma knockdown diminished osteoblast differentiation. MSCs that were treated with rosiglitazone did not preferentially differentiate into adipocytes. However, the rosiglitazone-mediated acceleration of osteoblast differentiation was followed by increased accumulation of reactive oxygen species and apoptosis. In contrast to the osteogenic lineage, cells of the adipogenic lineage were protected from this. Our data support a new concept on bone health that adds to the explanation of the clinically observed suppressive action of activated PPAR-gamma on bone and the associated phenomenon of bone marrow adipogenesis. This concept is based on a higher susceptibility of the osteogenic than the adipogenic lineage to oxidative stress and apoptosis that is preferentially triggered in the osteoblasts by activated PPAR-gamma.
骨髓脂肪生成是一种与衰老相关的现象，与骨质疏松症有关。后者是老年人中常见的骨骼疾病，会增加骨折风险和死亡率。人们广泛假设，其潜在的分子机制包括间充质干细胞（MSCs）从成骨谱系向脂肪生成谱系的转变。谱系倾斜至少部分是转录变化的结果。核转录因子过氧化物酶体增殖物激活受体γ（PPAR-γ）被提议作为 MSC 谱系分化的主要决定因素，促进脂肪生成而牺牲成骨。在这里，我们发现 PPAR-γ出人意料地作用于促进人骨髓来源的 MSC 向成骨细胞分化。罗格列酮介导的激活和过表达 PPAR-γ均导致成骨细胞分化加速。相反，shRNAi 介导的 PPAR-γ敲低减少了成骨细胞分化。用罗格列酮处理的 MSC 不会优先分化为脂肪细胞。然而，罗格列酮介导的成骨细胞分化加速伴随着活性氧和细胞凋亡的增加。与成骨谱系相反，脂肪生成谱系的细胞不受此影响。我们的数据支持一个新的骨骼健康概念，该概念增加了对激活的 PPAR-γ对骨骼的临床观察到的抑制作用以及相关的骨髓脂肪生成现象的解释。该概念基于成骨细胞比脂肪生成细胞对氧化应激和凋亡的更高敏感性，而激活的 PPAR-γ优先在成骨细胞中触发这种敏感性。
