AS-605240 通过抑制骨吸收来缓解骨质疏松症。
AS-605240 Blunts Osteoporosis by Inhibition of Bone Resorption.
机构信息
Department of Orthopaedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, People's Republic of China.
Bone Development and Metabolism Research Center of Taizhou Hospital, Linhai, Zhejiang Province, People's Republic of China.
出版信息
Drug Des Devel Ther. 2023 Apr 27;17:1275-1288. doi: 10.2147/DDDT.S403231. eCollection 2023.
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.
背景
骨质疏松症是一种代谢性骨病。破骨细胞在骨质疏松症的发病机制中起着重要作用。AS-605240（AS）是一种小分子 PI3K-γ 抑制剂，与泛 PI3K 抑制剂相比毒性较小。AS 还具有多种生物学作用，包括抗炎、抗肿瘤和心肌重塑促进作用。然而，AS 对破骨细胞的分化和功能的影响以及 AS 在治疗骨质疏松症患者中的作用尚不清楚。
目的
本研究旨在探讨 AS 是否抑制 M-CSF 和 RANKL 诱导的破骨细胞分化和骨吸收。接下来，我们评估 AS 对去卵巢（OVX）诱导的骨质疏松症小鼠模型中骨丢失的治疗效果。
方法
我们用含有不同 AS 浓度的破骨细胞分化培养基刺激骨髓来源的巨噬细胞 6 天或用 5μM AS 刺激不同时间。然后，我们进行抗酒石酸酸性磷酸酶（TRAP）染色、骨吸收测定、F-肌动蛋白环荧光、实时定量聚合酶链反应（RT-qPCR）和 Western blot（WB）。接下来，用不同 AS 浓度刺激 MC3T3-E1s（成骨前体细胞）分化为成骨细胞。然后，我们对这些细胞进行碱性磷酸酶（ALP）染色、RT-qPCR 和 WB。我们建立了 OVX 诱导的骨质疏松症小鼠模型，并给小鼠用 20mg/kg 的 AS 进行治疗。最后，我们提取股骨并进行 micro-CT 扫描、H&E 和 TRAP 染色。
结果
AS 通过抑制 PI3K/Akt 信号通路抑制 RANKL 触发的破骨细胞形成和骨吸收。此外，AS 增强了体内 OVX 诱导的成骨细胞分化并抑制了骨丢失。
结论
AS 抑制了小鼠破骨细胞的产生并增强了成骨细胞的分化，为治疗骨质疏松症患者提供了一种新的治疗方法。
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