Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing
Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing
复制标题
DOI：
10.1002/jcp.28321
复制
发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Fahlgren, Anna
中科院分区：
文献类型：
--
作者：
Amirhosseini, Mehdi;Bernhardsson, Magnus;Fahlgren, Anna
细胞周期蛋白依赖性激酶8(CDK8)是一种依赖于环境和细胞类型的介质复合体相关的转录调节因子。虽然最初的研究是作为潜在的癌症治疗药物，但据报道，CDK8及其类似物CDK19的一些抑制剂会影响成骨细胞的谱系和骨形成。本研究观察了两种选择性CDK8/19抑制剂在体外对破骨细胞生成和成骨细胞的影响，并进一步评价了CDK8/19抑制剂局部治疗对大鼠松质骨愈合的影响。CDK8/19抑制剂对小鼠骨髓来源的巨噬细胞和原代小鼠成骨细胞的增殖均无影响。抑制CDK8/19可显著抑制核因子B受体激活剂配体(RANKL)诱导的小鼠骨髓基质细胞破骨细胞分化，同时伴有抗酒石酸酸性磷酸酶(TRAP)活性降低和I型胶原C端肽水平的降低。伴随着RANKL刺激的骨髓基质细胞中PU.1、RANK、NF-B、活化T细胞核因子1(NFATc1)、树突状细胞特异性跨膜蛋白(DC-STAMP)、TRAP和组织蛋白K的下调。下调破骨细胞前体的RANK及其下游信号使CDK8/19抑制剂成为抗代谢药物，以阻止过度的破骨细胞生成。在小鼠原代成骨细胞中，抑制CDK8/19不影响分化，但通过促进碱性磷酸酶活性和下调矿化负调控因子骨桥蛋白来促进成骨细胞的矿化。在大鼠胫骨中，CDK8/19抑制剂局部应用可促进松质骨再生。我们的数据表明，CDK8/19的抑制剂有可能发展成为限制骨溶解和促进骨再生的治疗药物。
Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8and its paralog CDK19have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8/19 inhibitor affects cancellous bone healing in rats. CDK8/19 inhibitors did not alter the proliferation of neither mouse bone marrow-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor B (NF-B) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-B, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.