Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes
Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes
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DOI：
10.1101/gad.1224204
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发表时间：
2004-10-01
影响因子：
10.5
通讯作者：
Kawaguchi, H
中科院分区：
文献类型：
--
作者：
Chikuda, H;Kugimiya, F;Kawaguchi, H
Komeda小型大鼠石川（KMI）是由常染色体隐性突变mri引起的自然发生的突变体，其表现出纵向生长迟缓。在这里，我们确定了mri突变作为大鼠基因编码cGMP依赖性蛋白激酶II（cGKII）的缺失。KMl显示生长板扩张和骨愈合受损，伴有有丝分裂后但非肥大软骨细胞的异常积累。离体培养的KMI软骨细胞再现的分化障碍，这是恢复通过引入腺病毒介导的cGKII基因。Sox 9的表达，肥大分化的抑制性调节，持续在有丝分裂后的软骨细胞的KMI生长板的细胞核。在培养系统中的转染实验表明，cGKII减弱了Sox 9诱导软骨细胞分化的功能，并抑制软骨细胞的肥大分化。Sox 9的这种衰减是由于cGKII抑制Sox 9的核进入。通过RNA干扰沉默Sox 9，培养的KMI软骨细胞的分化受损得到恢复。因此，本研究首次揭示了cGKII作为分子开关的新作用，通过减弱Sox 9功能将软骨细胞增殖的停止和肥大分化的开始偶联。
The Komeda miniature rat Ishikawa (KMI) is a naturally occurring mutant caused by an autosomal recessive mutation mri, which exhibits longitudinal growth retardation. Here we identified the mri mutation as a deletion in the rat gene encoding cGMP-dependent protein kinase type II (cGKII). KMls showed an expanded growth plate and impaired bone healing with abnormal accumulation of postmitotic but nonhypertrophic chondrocytes. Ex vivo culture of KMI chondrocytes reproduced the differentiation impairment, which was restored by introducing the adenovirus-mediated cGKII gene. The expression of Sox9, an inhibitory regulator of hypertrophic differentiation, persisted in the nuclei of postmitotic chondrocytes of the KMI growth plate. Transfection experiments in culture systems revealed that cGKII attenuated the Sox9 functions to induce the chondrogenic differentiation and to inhibit the hypertrophic differentiation of chondrocytes. This attenuation of Sox9 was due to the cGKII inhibition of nuclear entry of Sox9. The impaired differentiation of cultured KMI chondrocytes was restored by the silencing of Sox9 through RNA interference. Hence, the present study for the first time shed light on a novel role of cGKII as a molecular switch, coupling the cessation of proliferation and the start of hypertrophic differentiation of chondrocytes through attenuation of Sox9 function.