Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal.
Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal.
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DOI：
10.1002/jor.21262
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发表时间：
2011-03
影响因子：
2.8
通讯作者：
Murakami, Shunichi
中科院分区：
文献类型：
--
作者：
Sebastian, Arjun;Matsushita, Takehiko;Kawanami, Aya;Mackem, Susan;Landreth, Gary E.;Murakami, Shunichi
FGFR 3的激活突变导致最常见的人类侏儒症：软骨发育不全和致死性发育不良。在软骨发育不全的小鼠模型中，最近的研究表明ERK MAPK通路（一种由FGFR 3激活的通路）导致骨生长减少。我们最近的研究表明，软骨细胞中增加的Fgfr 3和ERK MAPK信号传导也会导致颅底和椎骨中的软骨结合过早闭合，从而导致软骨发育不全时枕骨大孔和椎管的有时致命的狭窄。相反，ERK 1和ERK 2的减少或失活是否促进骨生长和延迟软骨结合闭合仍有待研究。在这项研究中，我们使用Col 2a 1-Cre和Col 2a 1-CreER转基因灭活ERK 1缺失小鼠软骨细胞中的ERK 2。我们发现软骨细胞中ERK 1和ERK 2的基因失活增强了软骨骨骼元件的生长。我们还发现软骨细胞中ERK 1和ERK 2的出生后失活延迟了软骨结合的闭合并扩大了椎管。这些观察结果使ERK 1和ERK 2成为治疗软骨发育不全和其他FGFR 3相关骨骼综合征的有吸引力的靶点。
Activating mutations in FGFR3 cause the most common forms of human dwarfism: achondroplasia and thanatophoric dysplasia. In mouse models of achondroplasia, recent studies have implicated the ERK MAPK pathway, a pathway activated by FGFR3, in creating reduced bone growth. Our recent studies have indicated that increased Fgfr3 and ERK MAPK signaling in chondrocytes also causes premature synchondrosis closure in the cranial base and vertebrae, accounting for the sometimes fatal stenosis of the foramen magnum and spinal canal in achondroplasia. Conversely, whether the decrease—or inactivation—of ERK1 and ERK2 promotes bone growth and delays synchondrosis closure remains to be investigated. In this study, we inactivated ERK2 in the chondrocytes of ERK1-null mice using the Col2a1-Cre and Col2a1-CreER transgenes. We found that the genetic inactivation of ERK1 and ERK2 in chondrocytes enhances the growth of cartilaginous skeletal elements. We also found that the postnatal inactivation of ERK1 and ERK2 in chondrocytes delays synchondrosis closure and enlarges the spinal canal. These observations make ERK1 and ERK2 an attractive target for the treatment of achondroplasia and other FGFR3-related skeletal syndromes.
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影响因子：
5.1
作者：
PAULI, RM;SCOTT, CI;LEBOVITZ, R
通讯作者：
LEBOVITZ, R
影响因子：
3.5
作者：
Matsushita, Takehiko;Wilcox, William R.;Murakami, Shunichi
通讯作者：
Murakami, Shunichi
影响因子：
2.8
作者：
Wilsman, NJ;Farnum, CE;Barreto, C
通讯作者：
Barreto, C
影响因子：
2.8
作者：
BREUR, GJ;VANENKEVORT, BA;WILSMAN, NJ
通讯作者：
WILSMAN, NJ
影响因子：
5.3
作者：
Matsushita, Takehiko;Chan, Yuk Yu;Murakami, Shunichi
通讯作者：
Murakami, Shunichi