肠道菌群代谢产物三甲胺N-氧化物在对骨质疏松症骨髓间充质干细胞功能的影响及与骨质疏松症损害中的作用关系

Role of intestinal microbiota metabolite trimethylamine N-oxide in functional impairment of bone marrow mesenchymal stem cells in osteoporosis damage

目的探讨三甲胺-N-氧化物对骨髓间充质干细胞功能的影响,以明确三甲胺-N-氧化物其在骨质疏松症发生、发展中的作用。方法采集骨质疏松症(OP)患者和健康志愿者血清标本,用ELISA法检测血清三甲胺N-氧化物(TMAO)水平,然后用三甲氧胺处理骨髓间充质干细胞,观察其对成脂和成骨分化、细胞增殖、活性氧释放和炎性细胞因子(IL-1β、IL-6、TNF-α)水平的影响。结果与健康对照组比较,OP骨质疏松症患者血清TMAO三甲胺N-氧化物水平显著升高。体外实验表明,TMAO三甲胺N-氧化物可明显促进骨髓间充质干细胞成脂,抑制成骨,增加活性氧释放,促进促炎细胞因子IL-1β、IL-6和TNF-α的产生,抑制细胞增殖。此外,我们还发现核因子-κB(NF-κB)信号通路的激活是诱导骨髓间充质干细胞产生促炎细胞因子、释放活性氧、成脂和成骨分化所必需的。结论TMAO水平与骨密度值呈显著负相关。TMAO通过上调NF-κB信号通路抑制骨髓间充质干细胞增殖,增加促炎性细胞因子的产生和活性氧的释放,抑制成骨分化,促进成脂分化,可能导致骨代谢失衡,加重骨丢失,进而导致骨质疏松症的发生。

Objective To investigate the effect of trimethylamine-N-oxide on the function of bone marrow mesenchymal stem cells,clarify the role of trimethylamine-N-oxide in the occurrence and development of osteoporosis.Methods Serum samples of osteoporosis patients and healthy volunteers were collected,and serum trimethylamine N-oxide levels were detected by ELISA.Then,bone marrow mesenchymal stem cells were treated with trimethoxide to observe their effects on adipogenic and osteogenic differentiation,cell proliferation,the release of reactive oxygen species and levels of inflammatory cytokines that IL-1β,IL-6 and TNF-α.Results Compared with healthy control group,serum trimethylamine n-oxide level was significantly increased in osteoporosis patients.In vitro experiments showed that trimethylamine n-oxide could significantly promote adipogenesis,inhibit osteogenesis,increase the release of reactive oxygen species,promote the production of pro-inflammatory cytokines IL-1β,IL-6 and TNF-α,and inhibit the proliferation of bone marrow mesenchymal stem cells.In addition,still found that activation of the nuclear factor-κB(NF-κB)signaling pathway was required to induce BMSCS to produce pro-inflammatory cytokines,release reactive oxygen species,and induce adipogenic and osteogenic differentiation.Conclusion There is a significant negative correlation between the level of trimethylamine-N-oxide and bone mineral density.Trimethylamine-n-oxide inhibits the proliferation of bone marrow mesenchymal stem cells by up-regulating NF-κB signaling pathway,increases the production of pro-inflammatory cytokines and the release of reactive oxygen species,inhibits osteogenic differentiation and promotes lipid differentiation,which may lead to bone metabolism imbalance and aggravate bone loss,leading to the occurrence of osteoporosis.