7,8-dihydroxyflavone Modulates Bone Formation and Resorption and Ameliorates Ovariectomy-Induced Osteoporosis

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Abstract

Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix and osteoprotegerin (OPG) were all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Fan Xue

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China

Competing interests
The authors declare that no competing interests exist.
Zhenlei Zhao

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China

Competing interests
The authors declare that no competing interests exist.
Yanpei Gu

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China

Competing interests
The authors declare that no competing interests exist.
Jianxin Han

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China

Competing interests
The authors declare that no competing interests exist.
Keqiang Ye

Emory University School of Medicine, Atlanta, United States

For correspondence
kye@emory.edu

Competing interests
The authors declare that no competing interests exist.
Ying Zhang

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China

For correspondence
yzhang@zju.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8533-4138

Funding

Key Research and Development Program of Guangdong Province (2019B020212001)

Ying Zhang

The funders had role in data collection and interpretation.

Ethics

Animal experimentation: All of the animals were handled according to approved Institutional Animal Care and Use Committee (IACUC) protocols (Aproval No.: IACUC-20190318-03) of Zhejiang Chinese Medical University. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.