Li Chang-Hong, Ma Zhen-Zhen, Jian Lei-Lei, Wang Xin-Yu, Sun Lin, Liu Xiang-Yuan, Yao Zhong-Qiang, Zhao Jin-Xia
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, PR China; Osteoporosis and Bone Metabolic Diseases Center, Peking University Third Hospital, Beijing 100191, PR China.
Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, PR China.
Int Immunopharmacol. 2021 Jan;90:107219. doi: 10.1016/j.intimp.2020.107219. Epub 2020 Dec 9.
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.
艾拉莫德是一种小分子药物，已被证明对治疗与骨质流失相关的疾病（如类风湿关节炎（RA））患者具有有效的骨保护作用。然而，艾拉莫德确切的骨保护机制仍有待确定。本研究的目的是更好地探索艾拉莫德骨保护的潜在机制。
用RANKL或TNF-α加M-CSF刺激C57/BL6小鼠的骨髓单核细胞。分别通过抗酒石酸酸性磷酸酶（TRAP）染色和骨吸收试验证实艾拉莫德对破骨细胞形态和功能的影响。通过逆转录-聚合酶链反应（RT-PCR）检测破骨细胞相关基因的表达，并通过蛋白质免疫印迹法检测信号通路的激活。我们使用骨质疏松症（卵巢切除术）和关节炎（改良TNF-α诱导破骨细胞生成）的啮齿动物模型来评估艾拉莫德在体内的骨保护作用。
在RANKL诱导破骨细胞生成的早期，艾拉莫德以剂量依赖性方式有效抑制破骨细胞形成，而艾拉莫德对M-CSF诱导的骨髓单核细胞增殖和RANK表达没有影响。早期和晚期添加艾拉莫德均显著降低骨吸收。给予艾拉莫德可预防去卵巢小鼠的骨质流失。艾拉莫德引起的破骨细胞生成阻滞是由于RANKL诱导的p38、细胞外信号调节激酶（ERK）和核因子κB（NF-κB）信号通路的废除。重要的是，艾拉莫德在体外也抑制TNF-α诱导的破骨细胞生成，并通过破坏NF-κB晚期核转位而不干扰IκBα降解在体内减弱破骨细胞生成。
艾拉莫德不仅通过干扰RANKL和TNF-α信号抑制破骨细胞生成，还抑制成熟破骨细胞的骨吸收。这些结果为艾拉莫德作为治疗RA尤其是预防骨质流失的独特治疗选择的治疗应用提供了有前景的证据。
