兰克尔
破骨细胞
骨吸收
骨髓
癌症研究
医学
体内
药理学
去卵巢大鼠
内分泌学
内科学
受体
生物
雌激素
激活剂(遗传学)
生物技术
作者
Changhong Li,Zhenzhen Ma,Leilei Jian,Xiaoyi Wang,Lin Sun,Xiangyuan Liu,Zhongqiang Yao,Jinxia Zhao
标识
DOI:10.1016/j.intimp.2020.107219
摘要
Iguratimod, a small molecular drug, has been proven to have effective bone protection for treatment of patients with bone loss-related diseases, such as rheumatoid arthritis (RA). However, the exact bone protective mechanism of iguratimod remains to be determined. The purpose of this study was to better explore the underlying mechanism of bone protection of iguratimod. Bone marrow monocytes from C57/BL6 mice were stimulated with either RANKL or TNF-α plus M-CSF. The effects of iguratimod on morphology and function of osteoclasts were confirmed by TRAP staining and bone resorption assay, respectively. The expression of osteoclast related genes was detected by RT-PCR and the activation of signal pathway was detected by Western blotting. We used rodent models of osteoporosis (ovariectomy) and of arthritis (modified TNF-α-induced osteoclastogenesis) to evaluate the osteoprotective effect of iguratimod in vivo. Iguratimod potently inhibited osteoclast formation in a dose-dependent manner at the early stage of RANKL-induced osteoclastogenesis, whereas iguratimod had no effect on M-CSF-induced proliferation and RANK expression in bone marrow monocytes. Bone resorption was significantly reduced by both early and late addition of iguratimod. Administration of iguratimod prevented bone loss in ovariectomized mice. The blockage of osteoclastogenesis elicited by iguratimod results from abrogation of the p38、ERK and NF-κB pathways induced by RANKL. Importantly, Iguratimod also dampened TNF-α-induced osteoclastogenesis in vitro and attenuated osteoclasts generation in vivo through disrupting NF-κB late nuclear translocation without interfering with IκBα degradation. Iguratimod not only suppresses osteoclastogenesis by interfering with RANKL and TNF-α signals, but also inhibits the bone resorption of mature osteoclasts. These results provided promising evidence for the therapeutic application of iguratimod as a unique treatment option against RA and especially in prevention of bone loss.
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