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) 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.

• Authors: Fan Xue, Zhenlei Zhao, Yanpei Gu, Jianxin Han, Keqiang Ye, Ying Zhang
• Journal: eLife (Elife) Vol. 10 (07 06 2021) ISSN: 2050-084X [Electronic] England
• PMID: 34227467 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021, Xue et al.

Chemical References

• 6,7-dihydroxyflavone
• Core Binding Factor Alpha 1 Subunit
• Flavones
• Osteoprotegerin
• Sp7 Transcription Factor
• beta Catenin
• Cyclin D1

Topics

• Animals
• Bone Remodeling
• Bone and Bones (metabolism)
• Cell Differentiation (drug effects)
• Cell Proliferation
• Core Binding Factor Alpha 1 Subunit
• Cyclin D1
• Disease Models, Animal
• Female
• Flavones (pharmacology)
• Osteoblasts (metabolism)
• Osteoclasts (metabolism)
• Osteogenesis (drug effects, genetics)
• Osteoporosis (metabolism)
• Osteoprotegerin
• Ovariectomy (adverse effects)
• Rats
• Sp7 Transcription Factor (metabolism)
• Wnt Signaling Pathway
• beta Catenin (genetics, metabolism)