LDC000067 suppresses RANKL-induced osteoclastogenesis in vitro and prevents LPS-induced osteolysis in vivo
LDC000067 suppresses RANKL-induced osteoclastogenesis in vitro and prevents LPS-induced osteolysis in vivo
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LDC000067 在体外抑制 RANKL 诱导的破骨细胞生成，并在体内防止 LPS 诱导的骨溶解
DOI：
10.1016/j.intimp.2019.105826
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Jinzhong Ma
中科院分区：
文献类型：
--
作者：
Song Xue;Qing Shao;Libo Zhu;Yafei Jiang;Cong Wang;Bao Xue;Haiming Lu;Weilin Sang;Jinzhong Ma
骨稳态需要成骨和破骨细胞生成之间的动态平衡，而溶骨性疾病主要归因于异常的破骨细胞生成和骨吸收。越来越多的证据表明，细胞周期蛋白依赖性激酶9（CDK 9）在不影响细胞周期的情况下调节一些炎症性疾病。CDK 9的特异性抑制剂LDC 000067（缩写为LDC 067）是否有助于预防溶骨性疾病尚未完全阐明。有趣的是，本研究表明，LDC 067在体外抑制了核因子-κB配体受体激活因子（RANKL）诱导的破骨细胞生成和骨吸收，并抑制了破骨细胞相关标志基因如组织蛋白酶K（CTSK）、抗酒石酸酸性磷酸酶（TRAP）、树突细胞特异性跨膜蛋白（DCs）的表达。（DC-STAMP）、V-ATP酶D2、降钙素受体（CTR）和活化T细胞胞质核因子1（NFATc 1）。LDC 067的骨保护作用可以部分地通过其抑制核因子-κ B（NF-κB）介导的NFATc 1通过AKT信号通路的活化来解释。与体外获得的结果一致，观察到用LDC 067抑制CDK 9延迟软骨下骨溶解并显著改善LPS诱导的小鼠颅骨骨溶解。总的来说，这些结果突出了LDC 067在预防溶骨性疾病中的积极作用，并表明这种CDK 9抑制剂可能是一种有前途的治疗剂。
Bone homeostasis requires a dynamic balance between osteogenesis and osteoclastogenesis, and osteolytic disorders are mainly attributed to aberrant osteoclastogenesis and bone resorption. Accumulating evidence has demonstrated that cyclin-dependent kinase 9 (CDK9) regulates some inflammatory diseases without affecting the cell cycle. Whether the specific inhibitor of CDK9, LDC000067 (abbreviated as LDC067), helps to prevent from osteolytic disorders has not been fully elucidated. Interestingly, this study demonstrated that LDC067 inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption in vitro, and suppressed the expression of osteoclast-related marker genes such as cathepsin K (CTSK), tartrate-resistant acid phosphatase (TRAP), dendrite cell-specific transmembrane protein (DC-STAMP), V-ATPase D2, calcitonin receptor (CTR) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). The bone protective effects of LDC067 can be partly explained by its suppression of nuclear factor-kappa B (NF-κB)-mediated NFATc1 activation via AKT signalling pathway. In keeping with the results obtained in vitro, inhibition of CDK9 with LDC067 was observed to delay subchondral osteolysis and substantially ameliorate LPS-induced osteolysis in murine calvaria. Collectively, these results highlight the positive effects of LDC067 in preventing osteolytic disorders and indicate that this CDK9 inhibitor may a promising therapeutic agent.