The SFRP1 Inhibitor WAY‐316606 Attenuates Osteoclastogenesis Through Dual Modulation of Canonical Wnt Signaling
The SFRP1 Inhibitor WAY‐316606 Attenuates Osteoclastogenesis Through Dual Modulation of Canonical Wnt Signaling
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DOI：
10.1002/jbmr.4435
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发表时间：
2021-09
影响因子：
6.2
通讯作者：
Qingliang Ma;Shiyu Wang;Ziang Xie;Yang Shen;B. Zheng;Chao Jiang;Pu-tao Yuan;Congcong Yu;Liangping Li;Xiangde Zhao;Junxin Chen;A. Qin;S. Fan;Z. Jie
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作者：
Qingliang Ma;Shiyu Wang;Ziang Xie;Yang Shen;B. Zheng;Chao Jiang;Pu-tao Yuan;Congcong Yu;Liangping Li;Xiangde Zhao;Junxin Chen;A. Qin;S. Fan;Z. Jie
骨质疏松症是一种值得注意的年龄相关性疾病，由骨生成和破骨细胞生成失衡引起，对个人和社会都是严重的经济负担。迫切需要对骨吸收和矿化具有双重作用的小分子药物。分泌型卷曲相关蛋白1（SFRP 1）是一种众所周知的经典Wnt信号传导的细胞外阻遏物，据报道可调节骨生成。全局SFRP 1敲除小鼠显示出显著升高的骨量。尽管破骨细胞（OCs）表达并分泌SFRP 1，但OCs产生的SFRP 1在破骨细胞发生和骨质疏松症中的作用仍不清楚。在这项工作中，发现与健康对照组相比，骨质疏松症患者的SFRP 1水平增加。WAY-316606（WAY）对SFRP 1的药理学抑制作用-在体外减弱破骨细胞生成和骨吸收。OC特异性基因的表达被SFRP 1抑制剂WAY抑制。细胞外和细胞内的SFRP 1都可以阻断经典Wnt信号通路的激活，并通过双重作用逆转经典Wnt的沉默状态，从而抑制破骨细胞的生成并促进成骨。在卵巢切除（OVX）小鼠模型中观察到严重的骨质减少，WAY治疗有效改善了OVX诱导的骨质疏松症。总之，这项工作发现SFRP 1支持OC分化和功能，WAY可以通过双重调节经典Wnt信号传导来减弱这种分化和功能，这表明其具有治疗潜力。© 2021美国骨与矿物质研究学会（ASBMR）。
Osteoporosis, a noteworthy age‐related disease induced by imbalanced osteogenesis and osteoclastogenesis, is a serious economic burden on both individuals and society. Small molecule drugs with dual effects on both bone resorption and mineralization are pressingly needed. Secreted frizzled‐related protein 1 (SFRP1), a well‐known extracellular repressor of canonical Wnt signaling, has been reported to regulate osteogenesis. Global SFRP1 knockout mice show significantly elevated bone mass. Although osteoclasts (OCs) express and secrete SFRP1, the role of SFRP1 produced by OCs in osteoclastogenesis and osteoporosis remains unclear. In this work, the levels of SFRP1 were found to be increased in patients with osteoporosis compared with healthy controls. Pharmacological inhibition of SFRP1 by WAY‐316606 (WAY)‐ attenuated osteoclastogenesis and bone resorption in vitro. The expressions of OC‐specific genes were suppressed by the SFRP1 inhibitor, WAY. Mechanistically, both extracellular and intracellular SFRP1 could block activation of the canonical Wnt signaling pathway, and WAY reverse the silent status of canonical Wnt through dual effects, leading to osteoclastogenesis inhibition and osteogenesis promotion. Severe osteopenia was observed in the ovariectomized (OVX) mouse model, and WAY treatment effectively improved the OVX‐induced osteoporosis. In summary, this work found that SFRP1 supports OC differentiation and function, which could be attenuated by WAY through dual modulation of canonical Wnt signaling, suggesting its therapeutic potential. © 2021 American Society for Bone and Mineral Research (ASBMR).