Zhang Qiang, Tang Xinqiao, Liu Zhong, Song Xiaoxia, Peng Dan, Zhu Wei, Ouyang Zhengxiao, Wang Wanchun
Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Orthopedics, Xiangtan Central Hospital, Xiangtan, China.
Front Pharmacol. 2018 Sep 11;9:1028. doi: 10.3389/fphar.2018.01028. eCollection 2018.
Bone homeostasis and resorption is regulated by the proper activation of osteoclasts, whose stimulation largely depends on the receptor activator of nuclear factor κB ligand (RANKL)-RANK signaling. Herein, for the first time, we showed that interferon regulatory factor (Irf)-3 was intimately involved in RANKL-induced osteoclast formation. In addition, hesperetin (Hes) derived from citrus fruit could inhibit RANKL-induced osteoclast differentiation and maturation among three types of osteoclast precursors with inhibited formation of F-actin rings and resorption pits on bone slices. More importantly, by using SP600125, a selective Jnk inhibitor, we showed that Hes was able to significantly attenuate the Jnk downstream expression of Irf-3 and c-Jun, thereby inactivating NF-κB/MAPK signaling and transcriptional factor NFATc-1, leading to suppression of osteoclast-specific genes, which resulted in impaired osteoclastogenesis and functionality. An ovariectomized (OVX) osteoporosis mouse model demonstrated that Hes could increase trabecular bone volume fractions (BV/TV), trabecular thickness, and trabecular number, whereas it decreased trabecular separation in OVX mice with well-preserved trabecular bone architecture and decreased levels of TRAP-positive osteoclasts. This is further evidenced by the diminished serum expression of bone resorption marker CTX and enhanced production of osteoblastic ALP . Taken together, these results suggested that Hes could inhibit Jnk-mediated Irf-3/c-Jun activation, thus attenuating RANKL-induced osteoclast formation and function both and .
骨稳态和骨吸收由破骨细胞的适当激活来调节，破骨细胞的刺激很大程度上取决于核因子κB受体激活剂配体（RANKL）-RANK信号通路。在此，我们首次表明干扰素调节因子（Irf）-3密切参与RANKL诱导的破骨细胞形成。此外，源自柑橘类水果的橙皮素（Hes）可抑制RANKL诱导的三种破骨细胞前体的破骨细胞分化和成熟，抑制骨切片上F-肌动蛋白环和吸收陷窝的形成。更重要的是，通过使用选择性Jnk抑制剂SP600125，我们发现Hes能够显著减弱Irf-3和c-Jun的Jnk下游表达，从而使NF-κB/MAPK信号通路和转录因子NFATc-1失活，导致破骨细胞特异性基因受到抑制，进而导致破骨细胞生成和功能受损。卵巢切除（OVX）骨质疏松小鼠模型表明，Hes可增加小梁骨体积分数（BV/TV）、小梁厚度和小梁数量，而降低OVX小鼠的小梁间距，同时保留良好的小梁骨结构，并降低抗酒石酸酸性磷酸酶（TRAP）阳性破骨细胞水平。骨吸收标志物CTX血清表达降低和成骨细胞碱性磷酸酶（ALP）产生增加进一步证明了这一点。综上所述，这些结果表明，Hes可抑制Jnk介导的Irf-3/c-Jun激活，从而在体内和体外减弱RANKL诱导的破骨细胞形成和功能。
