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Updated: Nov 10, 2025
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
LY3023414 inhibits both osteogenesis and osteoclastogenesis through the PI3K/Akt/GSK3 signalling pathway
Xiaojun Chen1, Wei Chen1, Zin Mar Aung1
1Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Aims:
LY3023414 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.
Methods:
The 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.
Results:
LY3023414 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.
Conclusion:
LY3023414 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.
Insights
The novel cancer drug LY3023414 inhibits bone formation (osteogenesis) and bone resorption (osteoclastogenesis) by blocking the PI3K/Akt/GSK3 pathway. This dual action may have implications for both therapeutic benefits and side effects in cancer patients.
Area of Science:
- Bone biology and cancer therapeutics.
- Investigating the effects of targeted cancer drugs on skeletal physiology.
Background:
- LY3023414 is an oral dual inhibitor of PI3K/mTOR, developed for advanced cancers.
- Its impact on bone modeling and remodeling remains largely uncharacterized.
Purpose of the Study:
- To elucidate the role of LY3023414 in regulating osteogenesis and osteoclastogenesis.
- To explore the underlying molecular mechanisms of its effects on bone cells.
Main Methods:
- Utilized murine preosteoblast (MC3T3-E1) and bone marrow-derived macrophage (BMM) cell lines.
- Assessed cell proliferation, differentiation, bone resorption, and gene expression (qRT-PCR).
- Investigated the PI3K/Akt/GSK3 pathway via western blot and siRNA knockdown of Akt1/Akt2.
Main Results:
- LY3023414 suppressed osteogenesis and osteoclastogenesis by inhibiting PI3K/Akt/GSK3 signaling.
- The drug primarily inhibited osteoclast formation, not mature osteoclast function.
- Osteogenesis was suppressed during both early differentiation and late calcification stages.
- Akt1 and Akt2 knockdown synergistically impaired both osteogenic and osteoclastogenic processes.
Conclusions:
- LY3023414 effectively suppresses both bone formation and resorption via the PI3K/Akt/GSK3 pathway.
- These findings highlight potential dual benefits and risks of LY3023414 in clinical cancer treatment.
- Understanding these effects is crucial for managing skeletal health in patients receiving this therapy.
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