7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

• Type of Material: Article
• Authors: Fan Xue, Zhejiang University; Zhenlei Zhao, Zhejiang University; Yanpei Gu, Zhejiang University; Jianxin Han, Zhejiang University; Keqiang Ye, Emory University; Ying Zhang, Zhejiang University
• Language: English
• Date: 2021-07-06
• Publisher: eLIFE SCIENCES PUBL LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2021, Xue et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.64872
• Title of Journal or Parent Work: ELIFE
• Volume: 10
• Grant/Funding Information: This paper was supported by the following grant:; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.; Key Research and Development Program of Guangdong Province 2019B020212001 to Ying Zhang.
• Keywords: Biology; RECEPTORS; NEUROTROPHIC FACTOR; METABOLISM; MEMORY DEFICITS; Life Sciences & Biomedicine - Other Topics; EXPRESSION; WNT; OSTEOCLAST DIFFERENTIATION; MOUSE MODEL; TRKB; Life Sciences & Biomedicine; Science & Technology; ACTIVATION
• Research Categories: Agriculture, Food Science and Technology; Health Sciences, Nutrition

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) was 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.