Ca2+/Calmodulin-dependent kinase II signaling causes skeletal overgrowth and premature chondrocyte maturation
Ca2+/Calmodulin-dependent kinase II signaling causes skeletal overgrowth and premature chondrocyte maturation
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DOI：
10.1016/j.ydbio.2008.02.007
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发表时间：
2008-05-01
影响因子：
2.7
通讯作者：
Hartmann, Christine
中科院分区：
文献类型：
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作者：
Taschner, Michael J.;Rafigh, Mehran;Hartmann, Christine
脊椎动物四肢的长骨起源于软骨模板，并通过软骨内骨化过程形成。这个过程需要软骨细胞经历从增殖到有丝分裂后前肥大到成熟肥大软骨细胞的渐进成熟。对增殖和成熟的协调控制调节骨骼元素的生长。各种信号和途径参与了这些过程的协调，但潜在的细胞内分子机制往往并不完全清楚。在这里，我们证明了在鸡使用复制能力逆转录病毒，钙/钙调蛋白依赖性激酶II（CaMKII）的组成性激活在发展中的翅膀导致与软骨细胞的过早分化相关的骨骼元素的伸长。软骨细胞的过早成熟是与下调4细胞周期调节因子和上调软骨细胞成熟标志物相关的组成型CaMKII信号传导的细胞自主效应。相反，骨骼元件的伸长是由编码甲状旁腺激素相关肽的印度刺猬应答基因的非细胞自主上调引起的。通过过度表达抑制肽减少内源性CaMKII活性导致与软骨细胞成熟延迟相关的骨骼元素缩短。因此，CaMKII是调节软骨细胞成熟的细胞内信号传导途径的重要组成部分。(C)2008年爱思唯尔公司All rights reserved.
The long bones of vertebrate limbs originate from cartilage templates and are formed by the process of endochondral ossification. This process requires that chondrocytes undergo a progressive maturation from proliferating to postmitotic prehypertrophic to mature, hypertrophic chondrocytes. Coordinated control of proliferation and maturation regulates growth of the skeletal elements. Various signals and pathways have been implicated in orchestrating these processes, but the underlying intracellular molecular mechanisms are often not entirely known. Here we demonstrated in the chick using replication-competent retroviruses that constitutive activation of Calcium/Calmodulin-dependent kinase II (CaMKII) in the developing wing resulted in elongation of skeletal elements associated with premature differentiation of chondrocytes. The premature maturation of chondrocytes was a cell-autonomous effect of constitutive CaMKII signaling associated with down-regulation 4 cell-cycle regulators and up-regulation of chondrocyte maturation markers, In contrast, the elongation of the skeletal elements resulted from a non-cell autonomous up-regulation of the Indian hedgehog responsive gene encoding Parathyroid-hormone-related peptide. Reduction of endogenous CaMKII activity by overexpressing an inhibitory peptide resulted in shortening of the skeletal elements associated with a delay in chondrocyte maturation. Thus, CaMKII is an essential component of intracellular signaling pathways regulating chondrocyte maturation. (C) 2008 Elsevier Inc. All rights reserved.