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Open AccessArticle

Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression

Division of Histology and Embryology, Joint Laboratory for Embryonic Development & Prenatal Medicine, Medical College, Jinan University, Guangzhou 510632, China
Department of Radiology, University of California San Diego, San Diego, CA 92103, USA
Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou 510632, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(7), 2518;
Received: 15 March 2020 / Revised: 30 March 2020 / Accepted: 2 April 2020 / Published: 4 April 2020
(This article belongs to the Special Issue Novel Extracellular and Intracellular Signalling Mechanisms in Bone)
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. View Full-Text
Keywords: microbiota dysbiosis; LPS; lipopolysaccharide; embryos; bone formation; osteopenia; Dlx5; RA; retinoic acid microbiota dysbiosis; LPS; lipopolysaccharide; embryos; bone formation; osteopenia; Dlx5; RA; retinoic acid
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You, L.; Zhu, L.; Li, P.-Z.; Wang, G.; Cai, H.; Song, J.; Long, D.; Berman, Z.; Lin, L.; Cheng, X.; Yang, X. Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression. Int. J. Mol. Sci. 2020, 21, 2518.

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