骨代谢中，破骨细胞是唯一能够吸收骨组织的细胞。破骨细胞的高活性可能导致骨质疏松和关节炎等骨溶解性疾病。虽然有几种治疗骨溶解性疾病的药物，但它们存在着局限性和多种副作用。Janus激酶抑制剂（JAK）XL019在骨髓纤维化和其他癌症治疗中显示出了有希望的结果。然而，它是否能对破骨细胞活性产生功能性影响还未得到证实。本研究在体外研究了XL019对破骨细胞生成和机制途径的影响。研究发现，XL019能够损害破骨细胞的形成，干扰骨吸收能力，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信号传导来抑制RANKL诱导的破骨细胞生成。分子对接分析解释了XL019如何与MAPK途径因子结合。此外，钛颗粒在小鼠颅骨上诱导骨溶解进一步证实了它对体内骨代谢的有益影响。总之，本研究证明了XL019通过MAPK信号通路可以有效抑制破骨细胞活性，成为骨代谢紊乱的有希望的替代药物治疗。版权所有 © 2023 Elsevier Inc. 保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.