The cyclin-dependent kinase inhibitor p57(Kip2) mediates proliferative actions of PTHrP in chondrocytes.
The cyclin-dependent kinase inhibitor p57(Kip2) mediates proliferative actions of PTHrP in chondrocytes.
复制标题
细胞周期蛋白依赖性激酶抑制剂 p57(Kip2) 介导软骨细胞中 PTHrP 的增殖作用。
DOI：
10.1172/jci21252
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Kronenberg,HenryM
中科院分区：
文献类型：
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作者：
MacLean,HelenE;Guo,Jun;Knight,MelissaC;Zhang,Pumin;Cobrinik,David;Kronenberg,HenryM
甲状旁腺素相关肽（PTHrP）是骨发育过程中软骨细胞增殖的正调节因子。在缺乏PTHrP的胚胎小鼠中，软骨细胞过早停止增殖，加速分化。由于缺乏细胞周期蛋白依赖性激酶抑制剂p57 Kip2的小鼠的骨表型与PTHrP无效表型相反，我们假设PTHrP在软骨细胞中的增殖作用可能是由相反的p57介导的。我们产生了p57/PTHrP-null胚胎，其表现出PTHrP-null表型的部分拯救。在大多数骨中，增殖软骨细胞的丢失逆转，PTHrP无效表型中发生的加速分化逆转。在PTHrP缺乏的情况下，p57 mRNA和蛋白在增殖的软骨细胞中上调。跖骨培养研究证实了PTHrP在模型中降低p57 mRNA和蛋白水平的作用，其中甲状旁腺激素（PTH）用作PTHrP的类似物，增加软骨细胞增殖速率和增殖域的长度。PTH治疗p57缺失的跖骨对圆形增殖软骨细胞的增殖率没有影响，但仍刺激柱状软骨细胞的增殖。这些研究表明PTHrP对软骨细胞增殖的速率和程度的影响至少部分是通过抑制p57表达来介导的。
Parathyroid hormone–related peptide (PTHrP) is a positive regulator of chondrocyte proliferation during bone development. In embryonic mice lackingPTHrP, chondrocytes stop proliferating prematurely, with accelerated differentiation. Because the bone phenotype of mice lacking the cyclin-dependent kinase inhibitor p57Kip2is the opposite of thePTHrP-null phenotype, we hypothesized that PTHrP’s proliferative actions in chondrocytes might be mediated by opposing p57. We generatedp57/PTHrP-null embryos, which showed partial rescue of thePTHrP-null phenotype. There was reversal of the loss of proliferative chondrocytes in most bones, with reversal of the accelerated differentiation that occurs in thePTHrP-null phenotype. p57 mRNA and protein were upregulated in proliferative chondrocytes in the absence of PTHrP. Metatarsal culture studies confirmed the action of PTHrP to decrease p57 mRNA and protein levels in a model in which parathyroid hormone (PTH), used as an analog of PTHrP, increased chondrocyte proliferation rate and the length of the proliferative domain. PTH treatment ofp57-null metatarsals had no effect on proliferation rate in round proliferative chondrocytes but still stimulated proliferation in columnar chondrocytes. These studies suggest that the effects of PTHrP on both the rate and extent of chondrocyte proliferation are mediated, at least in part, through suppression ofp57expression.