AS-605240 Blunts Osteoporosis by Inhibition of Bone Resorption

  • Drug Des Devel Ther. 2023 Apr 27;17:1275-1288. doi: 10.2147/DDDT.S403231.
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.
PMID: 37138583 DOI: 10.2147/DDDT.S403231
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.
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