AS-605240 Blunts Osteoporosis by Inhibition of Bone Resorption

Jiacheng Sun; Guoping Cai; Jinlong Shen; Pu Cheng; Jiapeng Zhang; Dengteng Jiang; Xianquan Xu; Fangying Lu; Lihua Chen; Haixiao Chen

doi:10.2147/DDDT.S403231

AS-605240 Blunts Osteoporosis by Inhibition of Bone Resorption

Drug Des Devel Ther. 2023 Apr 27:17:1275-1288. doi: 10.2147/DDDT.S403231. eCollection 2023.

Authors

Jiacheng Sun^#^{1

2}, Guoping Cai^#^{1

2}, Jinlong Shen^{1

2}, Pu Cheng^{1

2}, Jiapeng Zhang^{1

2}, Dengteng Jiang^{1

2}, Xianquan Xu^{1

2}, Fangying Lu^{1

2}, Lihua Chen^{1

2}, Haixiao Chen^{1

2}

Affiliations

¹ Department of Orthopaedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, People's Republic of China.
² Bone Development and Metabolism Research Center of Taizhou Hospital, Linhai, Zhejiang Province, People's Republic of China.

^# Contributed equally.

Abstract

Background: Osteoporosis is a metabolic bone disease. Osteoclasts are significantly involved in the pathogenesis of osteoporosis. AS-605240 (AS) is a small molecule PI3K-γ inhibitor and is less toxic compared to pan-PI3K inhibitors. AS also exerts multiple biological effects including anti-inflammatory, anti-tumor, and myocardial remodeling promotion. However, the involvement of AS in the differentiation and functions of osteoclasts and the effect of AS in treating patients with osteoporosis is still unclear.

Purpose: This study aimed to investigate if AS inhibits the differentiation of osteoclasts and resorption of the bones induced by M-CSF and RANKL. Next, we evaluated the therapeutic effects of AS on bone loss in ovariectomy (OVX)-induced osteoporosis mice models.

Methods: We stimulated bone marrow-derived macrophages with an osteoclast differentiation medium containing different AS concentrations for 6 days or 5μM AS at different times. Next, we performed tartrate-resistant acid phosphatase (TRAP) staining, bone resorption assay, F-actin ring fluorescence, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting (WB). Next, MC3T3-E1s (pre-osteoblast cells) were differentiated to osteoblast by stimulating the cells with varying AS concentrations. Next, we performed alkaline phosphatase (ALP) staining, RT-qPCR, and WB on these cells. We established an OVX-induced osteoporosis mice model and treated the mice with 20mg/kg of AS. Finally, we extracted the femurs and performed micro-CT scanning, H&E, and TRAP staining.

Results: AS inhibits the formation of osteoclasts and resorption of bone triggered by RANKL by inhibiting the PI3K/Akt signaling pathway. Furthermore, AS enhances the differentiation of osteoblasts and inhibits bone loss due to OVX in vivo.

Conclusion: AS inhibits osteoclast production and enhances osteoblast differentiation in mice, thus providing a new therapeutic approach for treating patients with osteoporosis.

Keywords: AS-605240; PI3K/Akt; PI3Kγ; osteoclast; osteoporosis.

MeSH terms

Animals
Bone Resorption* / drug therapy
Bone Resorption* / metabolism
Cell Differentiation
Female
Humans
Mice
Osteoclasts
Osteogenesis
Osteoporosis* / drug therapy
Osteoporosis* / metabolism
Ovariectomy
Phosphatidylinositol 3-Kinases / metabolism

Substances

Phosphatidylinositol 3-Kinases
5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione

Grants and funding

This study was supported by the Natural Science Foundation of Zhejiang Province (LY20H060006), the Experimental Animal Science Project of Zhejiang Province (LGD19H310001), the Medicine and Health Science and Technology plan projects in Zhejiang Province (2021KY390), the Basic Public Welfare Research Project of Zhejiang Province (LGF19H060004), the Medical Science and Technology Project of Zhejiang Province (2020KY347) and the Science and Technology Planning Program of Taizhou City (1802KY04).