Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway
Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway
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DOI：
10.1038/nm971
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发表时间：
2004-01-01
期刊：
影响因子：
82.9
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Yasoda, A;Komatsu, Y;Nakao, K
软骨发育不全是人类侏儒症最常见的遗传形式，目前还没有有效的治疗方法。C型利钠肽（CNP）是一种新发现的通过颗粒鸟苷酸环化酶GC-B调节软骨内骨生长的分子。在这里，我们表明软骨细胞中的CNP靶向过表达可以抵消软骨发育不全小鼠模型中的侏儒症，其中软骨中有激活的成纤维细胞生长因子受体3（FGFR-3）。CNP通过抑制FGF信号传导的MAPK途径纠正生长板中细胞外基质合成减少，从而预防软骨发育不全骨的缩短。CNP对介导软骨发育不全软骨细胞增殖降低和分化延迟的FGF信号转导的STAT-1通路无影响。这些结果表明，在软骨内骨形成中激活CNP-GC-B系统构成了人类软骨发育不全的新治疗策略。
Achondroplasia is the most common genetic form of human dwarfism, for which there is presently no effective therapy. C-type natriuretic peptide (CNP) is a newly identified molecule that regulates endochondral bone growth through GC-B, a subtype of particulate guanylyl cyclase. Here we show that targeted overexpression of CNP in chondrocytes counteracts dwarfism in a mouse model of achondroplasia with activated fibroblast growth factor receptor 3 (FGFR-3) in the cartilage. CNP prevented the shortening of achondroplastic bones by correcting the decreased extracellular matrix synthesis in the growth plate through inhibition of the MAPK pathway of FGF signaling. CNP had no effect on the STAT-1 pathway of FGF signaling that mediates the decreased proliferation and the delayed differentiation of achondroplastic chondrocytes. These results demonstrate that activation of the CNP-GC-B system in endochondral bone formation constitutes a new therapeutic strategy for human achondroplasia.