Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan; Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.
Pharmacyclics, Inc., Research Department, Sunnyvale, CA 94085-4521, USA.
Bone. 2014 Mar;60:8-15. doi: 10.1016/j.bone.2013.11.025. Epub 2013 Dec 4.
Bone-resorbing osteoclasts play an essential role in normal bone homeostasis, as well as in various bone disorders such as osteoporosis and rheumatoid arthritis. Previously we showed that the Tec family of tyrosine kinases is essential for the differentiation of osteoclasts and the inhibition of Btk is a promising strategy for the prevention of the bone loss in osteoclast-associated bone disorders. Here we demonstrate that an orally available Btk inhibitor, ibrutinib (PCI-32765), suppresses osteoclastic bone resorption by inhibiting both osteoclast differentiation and function. Ibrutinib downregulated the expression of NFATc1, the key transcription factor for osteoclastogenesis, and disrupted the formation of the actin ring in mature osteoclasts. In addition, genome-wide screening revealed that Btk regulates the expression of the genes involved in osteoclast differentiation and function in both an NFATc1-dependent and -independent manner. Finally, we showed that ibrutinib administration ameliorated the bone loss that developed in a RANKL-induced osteoporosis mouse model. Thus, this study suggests ibrutinib to be a promising therapeutic agent for osteoclast-associated bone diseases.
破骨细胞在正常骨稳态以及各种骨疾病（如骨质疏松症和类风湿关节炎）中起着至关重要的作用。此前我们表明，Tec 家族酪氨酸激酶对于破骨细胞的分化是必不可少的，而抑制 Btk 是预防破骨细胞相关骨疾病中骨丢失的一种很有前途的策略。在这里，我们证明了一种口服 Btk 抑制剂依鲁替尼（PCI-32765）通过抑制破骨细胞分化和功能来抑制破骨细胞的骨吸收。依鲁替尼下调了 NFATc1 的表达，NFATc1 是破骨细胞生成的关键转录因子，并破坏了成熟破骨细胞中肌动蛋白环的形成。此外，全基因组筛选表明，Btk 以 NFATc1 依赖和非依赖的方式调节参与破骨细胞分化和功能的基因的表达。最后，我们表明依鲁替尼的给药改善了 RANKL 诱导的骨质疏松症小鼠模型中发生的骨丢失。因此，这项研究表明依鲁替尼是一种有前途的治疗破骨细胞相关骨疾病的药物。
