BACKGROUND Chronic steroid treatment causes an increase in visceral adiposity and osteoporosis. It is believed that steroids may alter a balance between differentiation of mesenchymal stem cells (MSCs) into either adipocytes or osteoblasts; however, the detailed molecular mechanisms are unclear. We previously identified Dexras1 as a critical factor that potentiates adipogenesis in response to glucocorticoids. Thus, in this study, we investigated the role of Dexras1 in maintaining the balance between chronic steroid treatment-associated adipogenesis and osteoporosis. MATERIAL AND METHODS We treated wild type (WT) and Dexras1 knockout (KO) mice with dexamethasone for five weeks followed by 60% HFD for additional two weeks with dexamethasone. The changes of glucocorticoid-induced body weight gain and osteoporosis were analyzed. Bone marrow derived stromal cells (BMSCs) and mouse embryonic fibroblasts (MEFs) extracted from WT and Dexras1 KO mice, as well as MC3T3-E1 pre-osteoblasts and osteoclasts differentiated from RAW264.7 were analyzed to further define the role of Dexras1 in osteoblasts and osteoclasts. RESULTS Dual-energy X-ray absorptiometry and micro-computed tomography analyses in murine femurs revealed that Dexras1 deficiency was associated with increased osteogenesis, concurrent with reduced adipogenesis. Furthermore, Dexras1 deficiency promoted osteogenesis of BMSCs and MEFs in vitro, suggesting that Dexras1 deficiency prevents steroid-induced osteoporosis. We also observed that Dexras1 downregulated SMAD signaling pathways, which reduced the osteogenic differentiation capacity of pre-osteoblast MC3T3-E1 cells into mature osteoblasts. CONCLUSION We propose that Dexras1 is critical for maintaining the equilibrium between adipogenesis and osteogenesis upon steroid treatment.

中文翻译：

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Dexras1在维持脂肪生成和成骨之间的平衡中起着关键作用。

背景技术长期类固醇治疗引起内脏肥胖和骨质疏松症的增加。据信类固醇可以改变间充质干细胞（MSC）分化为脂肪细胞或成骨细胞之间的平衡。但是，具体的分子机制尚不清楚。我们先前确定Dexras1是增强糖皮质激素响应脂肪生成的关键因素。因此，在这项研究中，我们研究了Dexras1在维持与类固醇治疗相关的慢性脂肪形成和骨质疏松之间的平衡的作用。材料和方法我们用地塞米松治疗野生型（WT）和Dexras1基因敲除（KO）小鼠5周，然后再用60％HFD用地塞米松治疗2周。分析了糖皮质激素引起的体重增加和骨质疏松的变化。分析了从WT和Dexras1 KO小鼠中提取的骨髓基质细胞（BMSC）和小鼠胚胎成纤维细胞（MEF），以及从RAW264.7分化而来的MC3T3-E1前破骨细胞和破骨细胞，以进一步确定Dexras1在成骨细胞中的作用和破骨细胞。结果在鼠股骨中进行双能X线吸收和显微计算机断层扫描分析发现Dexras1缺乏与成骨增加，脂肪形成减少有关。此外，Dexras1缺乏症在体外促进BMSCs和MEF的成骨作用，表明Dexras1缺乏症可预防类固醇诱导的骨质疏松症。我们还观察到Dexras1下调了SMAD信号通路，从而降低了成骨细胞前成骨细胞MC3T3-E1细胞成骨分化的能力。