7,8-dihydroxyflavone Modulates Bone Formation and Resorption and Ameliorates Ovariectomy-Induced Osteoporosis
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
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.
Reviewing Editor
- Carlos Isales, Medical College of Georgia at Augusta University, United States
Publication history
- Received: November 13, 2020
- Accepted: July 5, 2021
- Accepted Manuscript published: July 6, 2021 (version 1)
- Version of Record published: July 16, 2021 (version 2)
Copyright
© 2021, Xue et al.
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.
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