Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression
Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression
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菌群失调衍生的脂多糖通过视黄酸调节 DLX5 表达导致胚胎骨质减少
DOI：
10.3390/ijms21072518
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发表时间：
2020-04
影响因子：
5.6
通讯作者：
Yang Xuesong
中科院分区：
文献类型：
--
作者：
You Lingsen;Zhu Liwei;Li Pei-Zhi;Wang Guang;Cai Hongmei;Song Jinhuan;Long Denglu;Berman Zachary;Lin Li;Cheng Xin;Yang Xuesong
越来越多的证据表明，肠道菌群失调对人体健康有不利影响。然而，胚胎成骨是否受到母体肠道菌群失调的影响尚不清楚。在这项研究中，我们观察到在一个已建立的肠道微生物群失调模型中，脂多糖（LPS）水平升高导致骨骼发育迟缓。使用暴露于细菌失调衍生LPS的鸡胚胎，我们发现通过阿利新蓝和茜素红染色可以证明长骨发育受到限制。显微ct和组织学分析显示，LPS处理后，鸡胚胎指骨的骨小梁体积、骨密度和胶原蛋白生成减少，成骨细胞基因（Ocn、Runx2、Osx和Dlx5）表达受到抑制。原子力显微镜显示，在LPS作用下，MC3T3-E1细胞粗糙度降低，基质囊泡发育不良。上述成骨基因的表达在MC3T3-E1细胞中也受到抑制。高通量RNA测序表明，维甲酸（RA）可能在脂多糖诱导的骨质减少中发挥重要作用。RA的加入抑制了MC3T3-E1细胞中Dlx5的表达，暴露于LPS时也是如此。定量PCR、Western blot和免疫荧光染色结果显示，LPS或RA处理后，维甲酸受体α (RARα)表达上调，DLX5表达下调。MC3T3-E1细胞经LPS处理后，CYP1B1表达增加，可能与炎症因子增加，进而激活NF-κB信号通路有关。最终，用AGN193109阻断RA信号成功恢复了lps抑制的成骨细胞基因表达。综上所述，我们的数据表明，母体肠道菌群失调可以干扰骨骨化，其中由RA信号调节的Dlx5表达起重要作用。
Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an established mouse model of gut microbiota dysbiosis. Using chick embryos exposed to dysbacteriosis-derived LPS, we found restriction in the development of long bones as demonstrated by Alcian blue and alizarin red staining. Micro-CT and histological analysis exhibited decreased trabecular volume, bone mineral density, and collagen production, as well as suppressed osteoblastic gene expression (Ocn, Runx2, Osx, and Dlx5) in chick embryonic phalanges following LPS treatment. Atomic force microscopy manifested decreased roughness of MC3T3-E1 cells and poorly developed matrix vesicles (MVs) in presence of LPS. The expression of the aforementioned osteoblastic genes was suppressed in MC3T3-E1 cells as well. High-throughput RNA sequencing indicated that retinoic acid (RA) may play an important role in LPS-induced osteopenia. The addition of RA suppressed Dlx5 expression in MC3T3-E1 cells, as was also seen when exposed to LPS. Quantitative PCR, Western blot, and immunofluorescent staining showed that retinoic acid receptor α (RARα) was upregulated by LPS or RA treatment, while the expression of DLX5 was downregulated. CYP1B1 expression was increased by LPS treatment in MC3T3-E1 cells, which might be attributed to the increased inflammatory factors and subsequently activated NF-κB signaling. Eventually, blocking RA signals with AGN193109 successfully restored LPS-inhibited osteoblastic gene expression. Taken together, our data reveals that maternal gut microbiota dysbiosis can interfere with bone ossification, in which Dlx5 expression regulated by RA signaling plays an important role.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
DOI：
10.1016/j.matbio.2016.02.003
发表时间：
2016-05
期刊：
Matrix biology : journal of the International Society for Matrix Biology
影响因子：
--
作者：
Chaudhary SC;Kuzynski M;Bottini M;Beniash E;Dokland T;Mobley CG;Yadav MC;Poliard A;Kellermann O;Millán JL;Napierala D
通讯作者：
Napierala D
影响因子：
3.7
作者：
Aisemberg J;Vercelli CA;Bariani MV;Billi SC;Wolfson ML;Franchi AM
通讯作者：
Franchi AM
微生物群衍生的脂多糖通过提高 Sox9 表达来延缓生长板中的软骨细胞肥大
影响因子：
5.6
作者：
Cheng, Xin;Li, Pei-Zhi;Yang, Xuesong
通讯作者：
Yang, Xuesong
DOI：
10.1016/b978-0-12-415853-5.00011-x
发表时间：
2021
期刊：
Marcus and Feldman's Osteoporosis
影响因子：
--
作者：
A. Boskey;P. Robey
通讯作者：
A. Boskey;P. Robey