Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo
Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo
复制标题
Nirogacestat 在体外抑制 RANKL 诱导的破骨细胞形成，并在体内减弱 LPS 诱导的骨吸收
DOI：
10.1016/j.yexcr.2019.06.015
复制
发表时间：
2019-09-01
影响因子：
3.7
通讯作者：
Zhang, Shanyong
中科院分区：
文献类型：
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作者：
Chen, Xuzhuo;Chen, Xinwei;Zhang, Shanyong
破骨细胞(OCs)启动的骨吸收在骨稳态中起着至关重要的作用。骨吸收异常可导致一系列疾病，包括骨关节炎、骨质疏松症和无菌性种植体周围松动。尼罗卡司他(PF-03084014，PF)是一种新型的伽玛分泌酶抑制剂，已用于治疗硬纤维瘤的II期临床试验。但其对异常骨吸收是否有治疗作用仍有待评价。本研究在体外研究PF对核因子-kB受体激活剂(RANKL)诱导的破骨细胞生成的调节作用，以及在体内对脂多糖(LPS)诱导的骨吸收的调节作用。研究发现，PF可在不引起细胞毒性的情况下抑制骨髓巨噬细胞(BMMS)的破骨细胞形成，抑制骨吸收，并下调破骨细胞特异性标志物降钙素受体(CTR)、抗酒石酸酸性磷酸酶(TRAP)、组织蛋白酶K(CTSK)、树突状细胞特异性跨膜蛋白(DC-STAMP)、ATP6v0d2(V-ATPase D2)和活化T细胞核因子1(NFATc1)的mRNA水平。此外，Notch2信号以及RANKL诱导的AKT信号在BMMS中受到显著抑制。与体外观察结果一致，我们发现PF能显著改善脂多糖诱导的骨吸收。综上所述，我们的研究表明PF在治疗溶骨性疾病方面有很大的潜力。
Bone resorption, initiated by osteoclasts (OCs), plays an essential role in bone homeostasis. The abnormalities of bone resorption may induce a series of diseases, including osteoarthritis, osteoporosis and aseptic peri-implant loosening. Nirogacestat (PF-03084014, PF), a novel gamma-secretase inhibitor, has been used in phase II clinical trial for treatment of desmoid tumor. However, whether it has the therapeutic effect on abnormal bone resorption remains to be evaluated. In this study, we investigated the role of PF in the regulation of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis in vitro, and the lipopolysaccharide (LPS)-induced bone resorption in vivo. It was found that PF could suppress the formation of osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, inhibit bone resorption and downregulate the mRNA level of osteoclast-specific markers, including calcitonin receptor (CTR), tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), dendritic cell-specific transmembrane protein (Dc-stamp), Atp6v0d2 (V-ATPase d2) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Furthermore, Notch2 signaling, as well as RANKL-induced AKT signaling was significantly inhibited in BMMs. Consistent with in vitro observation, we found that PF greatly ameliorated LPS-induced bone resorption. Taken together, our study demonstrated that PF has a great potential to be used in management of osteolytic diseases.