Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis

Zuoxing Wu; Xuedong Li; Xiaohui Chen; Xuemei He; Yu Chen; Long Zhang; Zan Li; Mengyu Yang; Guixin Yuan; Baohong Shi; Ning Chen; Na Li; Haotian Feng; Mengyu Zhou; Gang Rui; Feng Xu; Ren Xu

doi:10.3389/fphar.2022.1021714

Phosphatidyl Inositol 3-Kinase (PI3K)-Inhibitor CDZ173 protects against LPS-induced osteolysis

Front Pharmacol. 2023 Jan 6:13:1021714. doi: 10.3389/fphar.2022.1021714. eCollection 2022.

Authors

Zuoxing Wu^{1

2

3}, Xuedong Li⁴, Xiaohui Chen^{1

2

3}, Xuemei He², Yu Chen², Long Zhang², Zan Li⁵, Mengyu Yang², Guixin Yuan², Baohong Shi², Ning Chen⁶, Na Li^{1

2

3}, Haotian Feng⁷, Mengyu Zhou⁸, Gang Rui¹, Feng Xu⁹, Ren Xu^{1

2

3

10}

Affiliations

¹ Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
² The First Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cell, School of Medicine, Xiamen University, Xiamen, China.
³ Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, China.
⁴ Department of Medical Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China.
⁵ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.
⁶ Department of Endocrinology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
⁷ Inner Mongolia Dairy Technology Research Institute Co. Ltd., Hohhot, China.
⁸ Department of Dentistry, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁹ Department of Subject Planning, Ninth People's Hospital Shanghai, Jiaotong University School of Medicine, Shanghai, China.
¹⁰ Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China.

Abstract

A major complication of a joint replacement is prosthesis loosening caused by inflammatory osteolysis, leading to the revision of the operation. This is due to the abnormal activation of osteoclast differentiation and function caused by periprosthetic infection. Therefore, targeting abnormally activated osteoclasts is still effective for treating osteolytic inflammatory diseases. CDZ173 is a selective PI3K inhibitor widely used in autoimmune-related diseases and inflammatory diseases and is currently under clinical development. However, the role and mechanism of CDZ173 in osteoclast-related bone metabolism remain unclear. The possibility for treating aseptic prosthesis loosening brought on by inflammatory osteolysis illness can be assessed using an LPS-induced mouse cranial calcium osteolysis model. In this study, we report for the first time that CDZ173 has a protective effect on LPS-induced osteolysis. The data show that this protective effect is due to CDZ173 inhibiting the activation of osteoclasts in vivo. Meanwhile, our result demonstrated that CDZ173 had a significant inhibitory effect on RANKL-induced osteoclasts. Furthermore, using the hydroxyapatite resorption pit assay and podosol actin belt staining, respectively, the inhibitory impact of CDZ173 on bone resorption and osteoclast fusion of pre-OC was determined. In addition, staining with alkaline phosphatase (ALP) and alizarin red (AR) revealed that CDZ173 had no effect on osteoblast development in vitro. Lastly, CDZ173 inhibited the differentiation and function of osteoclasts by weakening the signal axis of PI3K-AKT/MAPK-NFATc1 in osteoclasts. In conclusion, our results highlight the potential pharmacological role of CDZ173 in preventing osteoclast-mediated inflammatory osteolysis and its potential clinical application.

Keywords: CDZ173; MAPK; Osteoclast; Osteolysis; PI3K.

Grants and funding

This work was supported in part by National Key R&D Program of China (2020YFA0112900 to RX), National Natural Science Foundation of China (81972034, 92068104 to RX and 82002262 to NL) and Natural Science Foundation of Fujian Province (2022J06003 to RX).