Hu Zi'ang, Chen Yilei, Song Lijiang, Yik Jasper H N, Haudenschild Dominik R, Fan Shunwu
Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Lawrence J. Ellison Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of California, Davis, Davis, CA, United States.
Front Pharmacol. 2018 May 3;9:174. doi: 10.3389/fphar.2018.00174. eCollection 2018.
Bone resorption and homeostasis is carried out by osteoclasts, whose differentiation and activity are regulated by the RANK/RANKL axis. Our previous studies using a mouse model of joint injury show that joint trauma induces local inflammation followed by bone remodeling. The transcription factor cyclin-dependent kinase 9 (CDK9) is the major regulator of inflammation, as CDK9 inhibitor flavopiridol effectively suppress injury-induced inflammatory response. The objective of this study was to investigate the underlying mechanism through which flavopiridol regulates bone resorption. The effects of CDK9 inhibition, by the specific-inhibitor flavopiridol, on bone resorption were determined using two distinct and clinically relevant bone remodeling models. The first model involved titanium particle-induced acute osteolysis, and the second model was ovariectomy-induced chronic osteoporosis. The effects and mechanism of CDK9 inhibition on osteoclastogenesis were examined using culture of bone marrow macrophages (BMMs). Our results indicated that flavopiridol potently suppressed bone resorption in both bone-remodeling models. In addition, CDK9 inhibition suppressed osteoclastogenesis of BMM and reduced their expression of osteoclast-specific genes. Finally, we determined that flavopiridol suppressed RANKL signaling pathway via inhibition of p65 phosphorylation and nuclear translocation of NF-κB. Summary, CDK9 is a potential therapeutic target to prevent osteolysis and osteoporosis by flavopiridol treatment.
骨吸收和骨稳态由破骨细胞执行，破骨细胞的分化和活性受RANK/RANKL轴调控。我们之前使用关节损伤小鼠模型的研究表明，关节创伤会引发局部炎症，随后是骨重塑。转录因子细胞周期蛋白依赖性激酶9（CDK9）是炎症的主要调节因子，因为CDK9抑制剂黄酮哌啶醇能有效抑制损伤诱导的炎症反应。本研究的目的是探究黄酮哌啶醇调节骨吸收的潜在机制。使用两种不同且与临床相关的骨重塑模型，确定了特异性抑制剂黄酮哌啶醇抑制CDK9对骨吸收的影响。第一个模型涉及钛颗粒诱导的急性骨溶解，第二个模型是卵巢切除诱导的慢性骨质疏松症。使用骨髓巨噬细胞（BMM）培养物研究了抑制CDK9对破骨细胞生成的影响和机制。我们的结果表明，黄酮哌啶醇在两种骨重塑模型中均能有效抑制骨吸收。此外，抑制CDK9可抑制BMM的破骨细胞生成，并降低其破骨细胞特异性基因的表达。最后，我们确定黄酮哌啶醇通过抑制p65磷酸化和NF-κB的核转位来抑制RANKL信号通路。总之，CDK9是通过黄酮哌啶醇治疗预防骨溶解和骨质疏松症的潜在治疗靶点。
