C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome
C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome
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DOI：
10.1093/hmg/ddy333
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发表时间：
2019-01-01
影响因子：
3.5
通讯作者：
Aoki, Yoko
中科院分区：
文献类型：
--
作者：
Inoue, Shin-ichi;Morozumi, Naomi;Aoki, Yoko
心脏-面部-皮肤（CFC）综合征是由BRAF、KRAS、MAP2K1和MAP2K2种系突变引起的遗传性疾病，其特征是生长迟缓、心脏缺陷、面部畸形和皮肤异常。我们之前报道过，表达CFC综合征相关突变Braf（Q241R）的敲入小鼠由于胃肠道功能障碍而表现出生长迟缓。然而，与生长迟缓相关的其他因素，包括软骨形成和内分泌特征，尚未被研究。在这里，我们发现3周和4周大的Braf（Q241R/+）小鼠体重和长度减少，胫骨近端生长板宽度也减少。此外，与Braf（+/+）小鼠相比，Braf（Q241R/+）小鼠生长板的增殖和肥厚软骨细胞带减少。免疫组织学分析显示，Braf（Q241R/+）小鼠的肥大软骨细胞中细胞外信号调节激酶（ERK）激活增强。Braf（Q241R/+）小鼠在3周龄和4周龄时血清中胰岛素样生长因子1 （IGF-1）和IGF结合蛋白3 （IGFBP-3）水平降低，与生长迟缓和生长板宽度减小一致。用c型利钠肽（CNP）治疗Braf（+/+）和Braf（Q241R/+）小鼠的体长和尾长增加，CNP是软骨内骨生长的刺激物和FGFR3-RAF1-MEK/ERK信号的有效抑制剂。综上所述，Braf（Q241R/+）小鼠软骨细胞中ERK活化和血清IGF-1/IGFBP-3低水平可能与生长迟缓有关。我们的数据还表明，CNP是CFC综合征的潜在治疗靶点。
Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf(Q241R,) showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old Braf(Q241R/+) mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in Braf(Q241R/+) mice compared with Braf (+/+) mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in Braf(Q241R/+) mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in Braf(Q241R/+) mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf(+/+) and Braf(Q241R/+) mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in Braf(Q241R/+) mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.