RANKL coordinates cell cycle withdrawal and differentiation in osteoclasts through the cyclin-dependent kinase inhibitors p27KIP1 and p21CIP1
RANKL coordinates cell cycle withdrawal and differentiation in osteoclasts through the cyclin-dependent kinase inhibitors p27KIP1 and p21CIP1
复制标题
DOI：
10.1359/jbmr.040321
复制
发表时间：
2004-08-01
影响因子：
6.2
通讯作者：
Ostrowski, MC
中科院分区：
文献类型：
--
作者：
Sankar, U;Patel, K;Ostrowski, MC
研究了RANKL信号转导对细胞周期进程和破骨细胞分化的协调作用。小鼠遗传模型的实验显示，RANKL促进依赖于细胞周期蛋白激酶抑制剂p27-KIP 1的破骨细胞前体的细胞周期撤回，但破骨细胞分化需要p27-KIP 1和p21-CIP 1。这些细胞周期蛋白抑制剂除了调节细胞周期退出外，还可以直接调节破骨细胞的分化。引言：RANKL刺激髓系单核前体细胞分化为多核破骨细胞，从而为研究细胞周期进程与细胞分化协调的基本问题提供了一个系统。使用缺乏功能性细胞周期蛋白抑制剂p27 KIP 1和p21 CIP 1表达的小鼠在体外和体内研究破骨细胞前体的细胞周期进展和分化。来自p27 KIP 1和p21 CIP 1缺陷小鼠的细胞实验表明，p27 KIP 1功能单独是破骨细胞前体RANKL介导的细胞周期退出所必需的，但来自这两个基因中任一个单一突变的小鼠的破骨细胞分化正常。相比之下，p21/p27双敲除小鼠发生骨硬化症，具有较少的破骨细胞，其表现出较低的TRACP活性和长骨中存在的异常细胞形态。此外，从p21/p27双敲除小鼠分离的破骨细胞祖细胞在体外RANKL介导的分化中存在缺陷，表达低水平的破骨细胞特异性基因，如TRACP和组织蛋白酶K。综上所述，这些数据表明p27 KIP 1和p21 CIP 1在破骨细胞分化中响应RANKL信号而发挥作用，与其在促进细胞周期退出中的作用不同。
The coordination of cell cycle progression and osteoclast differentiation by RANKL signaling was studied. Experiments with mouse genetic models revealed that RANKL promoted cell cycle withdrawal of osteoclast precursors dependent on the cyclin kinase inhibitor p27-KIP1, but that both p27-KIP1 and p21-CIP1 were required for osteoclast differentiation. These cyclin inhibitors may directly regulate osteoclast differentiation in addition to regulating cell cycle withdrawal.Introduction: RANKL stimulates mononuclear precursor cells of the myeloid lineage to differentiate into multinuclear osteoclasts, thus providing a system to study the fundamental problem of coordination of cell cycle progression with cell differentiation.Materials and Methods: Mice that lack expression of functional cyclin inhibitors p27KIP1 and p21CIP1 were used to study cell cycle progression and differentiation of osteoclast precursors in vitro and in vivo.Results and Conclusions: Experiments with cells derived from p27KIP1- and p21CIP1-deficient mice indicated that p27KIP1 function alone was necessary for RANKL-mediated cell cycle withdrawal by osteoclast precursors, but osteoclasts from mice with single mutations in either of these two genes differentiated normally. In contrast, p21/p27 double knockout mice developed osteopetrosis, with fewer osteoclasts that exhibited lower TRACP activity and abnormal cell morphology present in long bone. Moreover, isolated osteoclast progenitors from p21/p27 double knockout mice were defective in RANKL-mediated differentiation in vitro, expressing low levels of osteoclast-specific genes like TRACP and cathepsin K. Taken together, these data suggest p27KIP1 and p21CIP1 play roles in osteoclast differentiation in response to RANKL signaling distinct from their roles in promoting cell cycle withdrawal.