FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway
FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway
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DOI：
10.1093/hmg/ddn339
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发表时间：
2009-01-15
影响因子：
3.5
通讯作者：
Murakami, Shunichi
中科院分区：
文献类型：
--
作者：
Matsushita, Takehiko;Wilcox, William R.;Murakami, Shunichi
FGFR3的激活突变导致软骨发育不全和致死性发育不良，这是最常见的人类骨骼发育不良。在这些疾病中，椎管和枕骨大孔狭窄可导致严重的神经系统并发症。在这里，我们提供的证据表明，FGFR3和MAPK信号在软骨细胞促进软骨结合闭合和融合的骨化中心。我们在纯合子软骨发育不全和致死性发育不良的人类病例以及软骨发育不全的小鼠模型中观察到脊柱和颅底的软骨结合过早闭合。在这两个物种中，过早的软骨结合闭合与骨形成增加有关。小鼠软骨细胞特异性激活Fgfr 3可诱导软骨结合过早闭合，并增强软骨结合周围的成骨细胞分化。软骨细胞中的FGF信号以MAPK依赖性方式增加Bmp配体mRNA表达并降低Bmp拮抗剂mRNA表达，表明Bmp信号在骨形成增加中的作用。骨形成的增强会加速骨化中心的融合，限制软骨内骨的生长。因此，软骨发育不全杂合子患者的椎管和枕骨大孔狭窄可能通过过早的软骨结合闭合而发生。如果是这种情况，那么对软骨发育不全并发症的任何促生长治疗都必须在软骨结合闭合之前进行。
Activating mutations in FGFR3 cause achondroplasia and thanatophoric dysplasia, the most common human skeletal dysplasias. In these disorders, spinal canal and foramen magnum stenosis can cause serious neurologic complications. Here, we provide evidence that FGFR3 and MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers. We observed premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia and thanatophoric dysplasia as well as in mouse models of achondroplasia. In both species, premature synchondrosis closure was associated with increased bone formation. Chondrocyte-specific activation of Fgfr3 in mice induced premature synchondrosis closure and enhanced osteoblast differentiation around synchondroses. FGF signaling in chondrocytes increases Bmp ligand mRNA expression and decreases Bmp antagonist mRNA expression in a MAPK-dependent manner, suggesting a role for Bmp signaling in the increased bone formation. The enhanced bone formation would accelerate the fusion of ossification centers and limit the endochondral bone growth. Spinal canal and foramen magnum stenosis in heterozygous achondroplasia patients, therefore, may occur through premature synchondrosis closure. If this is the case, then any growth-promoting treatment for these complications of achondroplasia must precede the timing of the synchondrosis closure.