Flavopiridol Protects Bone Tissue by Attenuating RANKL Induced Osteoclast Formation.
Flavopiridol Protects Bone Tissue by Attenuating RANKL Induced Osteoclast Formation.
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DOI：
10.3389/fphar.2018.00174
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发表时间：
2018
影响因子：
5.6
通讯作者：
Fan S
中科院分区：
文献类型：
--
作者：
Hu Z;Chen Y;Song L;Yik JHN;Haudenschild DR;Fan S
骨吸收和体内平衡由破骨细胞进行，破骨细胞的分化和活性受RANK/RANKL轴调节。我们以前的研究使用小鼠关节损伤模型表明，关节创伤诱导局部炎症，然后是骨重建。转录因子细胞周期蛋白依赖性激酶9（CDK 9）是炎症的主要调节因子，因为CDK 9抑制剂flavopiridol有效抑制损伤诱导的炎症反应。本研究的目的是调查通过flavopiridol调节骨吸收的潜在机制。通过特异性抑制剂flavopiridol抑制CDK 9对骨吸收的影响使用两种不同的临床相关骨重建模型在体内测定。第一个模型涉及钛颗粒诱导的急性骨质溶解，第二个模型是卵巢切除术诱导的慢性骨质疏松症。采用体外培养的骨髓巨噬细胞（BMSCs）研究CDK 9抑制对破骨细胞生成的影响及其机制。我们的研究结果表明，flavopiridol有力地抑制骨吸收在体内骨重建模型。此外，CDK 9抑制抑制体外破骨细胞的BMM，并减少其破骨细胞特异性基因的表达。最后，我们确定flavopiridol通过抑制p65磷酸化和NF-κB核转位抑制RANKL信号通路。总之，CDK 9是通过flavopiridol治疗预防骨质溶解和骨质疏松症的潜在治疗靶点。
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 in vivo 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 in vitro culture of bone marrow macrophages (BMMs). Our results indicated that flavopiridol potently suppressed bone resorption in both in vivo bone-remodeling models. In addition, CDK9 inhibition suppressed in vitro 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.
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影响因子：
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作者：
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DOI：
10.1002/jbmr.2708
发表时间：
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DOI：
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发表时间：
2016-01-01
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影响因子：
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作者：
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通讯作者：
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