JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors.

IF 5 3区 医学 Q2 IMMUNOLOGY
Shinya Yari, Junichi Kikuta, Hotaka Shigyo, Yu Miyamoto, Daisuke Okuzaki, Yuki Furusawa, Masafumi Minoshima, Kazuya Kikuchi, Masaru Ishii
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引用次数: 4

Abstract

Background: Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging.

Methods: Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts.

Results: The JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions.

Conclusions: This is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.

Abstract Image

Abstract Image

Abstract Image

JAK抑制通过同时靶向成熟破骨细胞及其前体来改善骨破坏。
背景:类风湿性关节炎(RA)的特点是慢性炎症和由此产生的软骨/骨破坏,因为异常激活的破骨细胞。最近,几种Janus激酶(JAK)抑制剂的新疗法已被证明可以成功改善关节炎相关炎症和骨侵蚀,尽管它们限制骨破坏的作用机制尚不清楚。在这里,我们通过活体多光子成像检测了JAK抑制剂对成熟破骨细胞及其前体的影响。方法:对携带成熟破骨细胞或其前体报告基因的转基因小鼠局部注射脂多糖,诱导炎性骨破坏。小鼠用选择性抑制JAK1激活的JAK抑制剂ABT-317处理,然后用多光子显微镜进行活体成像。我们还使用RNA测序(RNA- seq)分析来研究JAK抑制剂对破骨细胞影响的分子机制。结果:JAK抑制剂ABT-317通过阻断成熟破骨细胞的功能和靶向破骨细胞前体向骨表面的迁移行为来抑制骨吸收。进一步详尽的RNA-Seq分析表明,在JAK抑制剂处理的小鼠中,破骨细胞前体的Ccr1表达受到抑制;CCR1拮抗剂J-113863改变破骨细胞前体的迁移行为,从而抑制炎症条件下的骨破坏。结论:这是第一个确定炎症条件下JAK抑制剂阻断骨破坏的药理作用的研究;这种抑制是有益的,因为它对成熟的破骨细胞和未成熟的破骨细胞前体都有双重作用。
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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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