Dataset Information

Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring.

ABSTRACT: The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation; however, the inhibitory effect of the Wnt pathway in osteoclastogenesis is largely unknown. Here, we demonstrate that Wnt7b, a potent Wnt ligand that enhances bone formation and increases bone mass, also abolishes osteoclastogenesis in vitro. Importantly, enforced expression of Wnt in bone marrow macrophage lineage cells significantly disrupts osteoclast formation and activity, which leads to a dramatic increase in bone mass. Mechanistically, Wnt7b impacts the glucose metabolic process and AKT activation during osteoclastogenesis. Thus, we demonstrate that Wnt7b diminishes osteoclast formation, which will be beneficial for osteoporosis therapy in the future.

SUBMITTER: Wu F

PROVIDER: S-EPMC8645835 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Wnt7b Inhibits Osteoclastogenesis <i>via</i> AKT Activation and Glucose Metabolic Rewiring.

Wu Fanzi F Li Boer B Hu Xuchen X Yu Fanyuan F Shi Yu Y Ye Ling L

Frontiers in cell and developmental biology 20211122

The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation ...[more]

PMID: 34881243

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Project description:AimsLY3023414 is a novel oral phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor designed for advanced cancers, for which a phase II clinical study was completed in March 2020; however, little is known about its effect on bone modelling/remodelling. In this study, we aimed to explore the function of LY3023414 in bone modelling/remodelling.MethodsThe function of LY3023414 was explored in the context of osteogenesis (bone formation by osteoblasts) and osteoclastogenesis (osteoclast formation and bone resorption). Murine preosteoblast MC3T3-E1 cell line and murine bone marrow-derived macrophage cells (BMMs) were subjected to different treatments. An MTS cell proliferation assay was used to examine the cytotoxicity. Thereafter, different induction conditions were applied, such as MCSF and RANKL for osteoclastogenesis and osteogenic media for osteogenesis. Specific staining, a bone resorption assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were subsequently used to evaluate the effect of LY3023414. Moreover, small interfering RNA (siRNA) was applied to knockdown Akt1 or Akt2 for further validation. Lastly, western blot was used to examine the exact mechanism of action.ResultsLY3023414 attenuated PI3K/protein kinase B (Akt)/GSK3-dependent activation of β-catenin and nuclear factor-activated T cell 1 (NFATc1) during osteogenesis and osteoclastogenesis, respectively. LY3023414 mainly inhibited osteoclast formation instead of mature osteoclast function. Moreover, it suppressed osteogenesis both in the early stage of differentiation and late stage of calcification. Similarly, gene knockdown of Akt isoforms by siRNA downregulated osteogenic and osteoclastogenic processes, indicating that Akt1 and Akt2 acted synergistically.ConclusionLY3023414 can suppress osteogenesis and osteoclastogenesis through inhibition of the PI3K/Akt/GSK3 signalling pathway, which highlights the potential benefits and side effects of LY3023414 for future clinical applications. Cite this article: Bone Joint Res 2021;10(4):237-249.

Dataset Information

Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring.

Publications

Wnt7b Inhibits Osteoclastogenesis <i>via</i> AKT Activation and Glucose Metabolic Rewiring.

Similar Datasets

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