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.
Highlights
Bone is a dynamic and continuously renewed tissue that undergoes significant modification throughout the life cycle
We performed a series of studies in vitro to demonstrate that 7,8-DHF promoted osteoblastic differentiation by interacting with tyrosine kinase B (TrkB) receptors and subsequently reinforcing the Wnt/β-catenin pathway in MC3T3-E1 cells
7,8-DHF improves bone mass, trabecular microarchitecture, tibial biomechanical properties and bone biochemical indexes in vivo as indicated in an OVX-induced osteoporosis rat model. 389 7,8-DHF has been identified as a promising small-molecular brain-derived neurotrophic factor (BDNF) mimetic compound, which mimics the physiological actions of BDNF via directly binding to the extracellular domain of TrkB to trigger TrkB receptor dimerization and autophosphorylation (Jang et al, 2010). 7,8-DHF
Summary
Bone is a dynamic and continuously renewed tissue that undergoes significant modification throughout the life cycle. Activation of the canonical Wnt/β-catenin signaling pathway involves recruitment of a degrading complex, stabilization of β-catenin, regulation of transcription factors such as Runx and Osterix, and activation of Wnt target genes (Baron & Kneissel, 2013; Karner & Long, 2017; Takada, Kouzmenko, & Kato, 2009). This pathway is active in osteoprogenitor cells or preosteoblasts such as MC3T3-E1 cells, and many signaling molecules in this pathway are developed as drug targets (Bhukhai et al, 2012; Zhou et al., 2020). The in vivo effects of 7,8-DHF on bone remodeling were examined in an ovariectomy-induced osteoporosis rat model
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