Xl019，一种新型的 JAK 抑制剂，通过 MAPK 信号通路抑制 RANKL 诱导的破骨细胞分化。
Xl019, a novel JAK inhibitor, suppressed osteoclasts differentiation induced by RANKL through MAPK signaling pathway.
机构信息
Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Center for Stomatology, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, China; Shanghai Research Institute of Stomatology, Shanghai, China.
Department of Orthodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
Biochem Pharmacol. 2023 Sep;215:115704. doi: 10.1016/j.bcp.2023.115704. Epub 2023 Aug 2.
Inbonemetabolism,osteoclastsare the only cellscapableofresorbingbone. Hyperactivity of osteoclasts may lead to osteolytic disease like osteoporosis and arthritis. Although there are several drugs for the treatment of osteolytic diseases, they have limitations and a variety of side effects. An inhibitor of Janus kinase (JAK), XL019, has shown promising results in the treatment of myelofibrosis and other cancers. But whether it can functionally impact osteoclast activity has not been proven. In this study, the effects of XL019 on osteoclastogenesis and the mechanism pathway were investigated in vitro. It was found that XL019 could impair osteoclasts formation, interfere with bone resorption ability and downregulate the osteoclast-specific genes and proteins expression. Furthermore, Western blot and molecular docking studies demonstrated that XL019 inhibited RANKL-induced osteoclastogenesis by suppressing MAPK signaling. A molecular docking analysis explained how XL019 binds to MAPK pathway factors. In addition, titanium particles induced calvarial osteolysis in mice further confirming its beneficial effect on bone homeostasis in vivo. In conclusion, this study demonstrates that Osteoclastactivity canbeeffectivelyinhibitedby XL019viaMAPK signalingpathway,making it a promising alternative pharmacologicaltreatmentfor bone metabolicdisorders.
在骨代谢中，破骨细胞是唯一具有吸收骨能力的细胞。破骨细胞的过度活跃可能导致骨质疏松症和关节炎等溶骨性疾病。虽然有几种药物可用于治疗溶骨性疾病，但它们存在局限性和多种副作用。Janus 激酶（JAK）抑制剂 XL019 在治疗骨髓纤维化和其他癌症方面显示出良好的效果。但它是否能对破骨细胞活性产生功能性影响尚未得到证实。在这项研究中，研究了 XL019 对体外破骨细胞生成的影响及其作用机制。结果发现，XL019 可以损害破骨细胞的形成，干扰骨吸收能力，并下调破骨细胞特异性基因和蛋白的表达。此外，Western blot 和分子对接研究表明，XL019 通过抑制 MAPK 信号通路抑制 RANKL 诱导的破骨细胞生成。分子对接分析解释了 XL019 如何与 MAPK 通路因子结合。此外，钛颗粒诱导小鼠颅骨骨溶解进一步证实了其在体内对骨稳态的有益作用。总之，本研究表明，XL019 通过 MAPK 信号通路可有效抑制破骨细胞活性，为骨代谢紊乱的潜在药物治疗提供了一种新的选择。
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