Zhang Kun, Wang Chunyu, Chen Yaxi, Ji Xiao, Chen Xiang, Tian Li, Yu Xijie
Laboratory of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
Endocrine. 2015 Sep;50(1):239-49. doi: 10.1007/s12020-015-0554-5. Epub 2015 Feb 21.
Obesity and osteoporosis are two common chronic diseases, however, the basis for the correlation between them remains largely unknown. The pro-inflammation cytokine tumor necrosis factor-alpha (TNF-α) plays important roles in lipid and bone metabolisms, which may be a good candidate in the correlation between obesity and osteoporosis. We investigated the pathological roles of TNF-α in high-fat diet (HFD)-induced bone loss. Wild-type (WT) mice and TNF-α knockout (TNF-α(-/-)) mice were fed with the standard diet or the HFD for 12 weeks. Bone marrow stromal cells (BMSCs) from both genotypes were induced to differentiate into osteoblasts and treated with palmitic acid (PA). Bone mass and microstructure of femurs were evaluated by micro-CT. Lipid and bone metabolisms were investigated by histological and plasma analyses, and real-time PCR. On the HFD, both TNF-α(-/-) and WT mice presented notable visceral obesity, dyslipidemia. Adipogenesis and osteoclastogenesis were enhanced, while osteoblastogenesis was reduced in both genotypes. However, the changes were significantly different between TNF-α(-/-) and WT mice after the HFD. The gain of body and fat-pad weight was less and adipocyte area was smaller by 22 % in TNF-α(-/-) mice. Osteoclast numbers and plasma CTX level were lower by 40 % and by 23 % in TNF-α(-/-) mice. There were more ALP positive cells in the PA-treated TNF-α(-/-) BMSCs. mRNA expression of PPAR-γ was lower while that of Runx2 was higher in the bone from TNF-α(-/-) HFD group and in the PA-treated TNF-α(-/-) BMSCs, compared to WT on the same treatment. Furthermore, femoral trabecular bone mass and trabecular bone number were significantly decreased in WT mice on the HFD, whereas they were increased by 1.56-fold and 1.53-fold, respectively, in TNF-α(-/-) mice on the same diet (P < 0.05). Our results demonstrated that TNF-α gene knockout retained HFD-induced femoral trabecular bone loss mainly by suppressing adipogenesis and osteoclastogenesis, and enhancing osteoblastogenesis, which suggests that TNF-α plays a critical role in the development of HFD-related bone metabolic disorders and it may be a new potential therapeutic target for obesity-related bone loss.
肥胖和骨质疏松是两种常见的慢性疾病，然而，它们之间相关性的基础在很大程度上仍不清楚。促炎细胞因子肿瘤坏死因子-α（TNF-α）在脂质和骨代谢中发挥重要作用，这可能是肥胖与骨质疏松之间相关性的一个良好候选因素。我们研究了TNF-α在高脂饮食（HFD）诱导的骨质流失中的病理作用。将野生型（WT）小鼠和TNF-α基因敲除（TNF-α(-/-)）小鼠分别喂食标准饮食或高脂饮食12周。诱导两种基因型的骨髓间充质干细胞（BMSC）分化为成骨细胞，并用棕榈酸（PA）处理。通过显微CT评估股骨的骨量和微观结构。通过组织学和血浆分析以及实时PCR研究脂质和骨代谢。在高脂饮食条件下，TNF-α(-/-)小鼠和WT小鼠均出现明显的内脏肥胖、血脂异常。两种基因型的脂肪生成和破骨细胞生成均增强，而成骨细胞生成减少。然而，高脂饮食后TNF-α(-/-)小鼠和WT小鼠之间的变化存在显著差异。TNF-α(-/-)小鼠的体重和脂肪垫重量增加较少，脂肪细胞面积小22%。TNF-α(-/-)小鼠的破骨细胞数量和血浆CTX水平分别降低40%和23%。在PA处理的TNF-α(-/-) BMSC中有更多的碱性磷酸酶阳性细胞。与相同处理的WT小鼠相比，TNF-α(-/-)高脂饮食组的骨骼以及PA处理的TNF-α(-/-) BMSC中PPAR-γ的mRNA表达较低，而Runx2的mRNA表达较高。此外，高脂饮食的WT小鼠股骨小梁骨量和小梁骨数量显著减少，而相同饮食的TNF-α(-/-)小鼠的股骨小梁骨量和小梁骨数量分别增加了1.56倍和1.53倍（P < 0.05）。我们的结果表明，TNF-α基因敲除主要通过抑制脂肪生成和破骨细胞生成以及增强成骨细胞生成来保留高脂饮食诱导的股骨小梁骨丢失，这表明TNF-α在高脂饮食相关的骨代谢紊乱发展中起关键作用，并且它可能是肥胖相关骨质流失的一个新的潜在治疗靶点。
