C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome
Autor: | Hiroaki Maeda, Kazunori Yoshikiyo, Naomi Morozumi, Yoko Aoki, Shin Ichi Inoue |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Heart Defects Congenital Proto-Oncogene Proteins B-raf medicine.medical_specialty medicine.drug_class MAP Kinase Signaling System medicine.medical_treatment MAP Kinase Kinase 2 MAP Kinase Kinase 1 MAP2K2 Biology 010402 general chemistry 01 natural sciences 03 medical and health sciences Mice Chondrocytes Ectodermal Dysplasia Internal medicine Genetics Extracellular Natriuretic peptide medicine Animals Humans Insulin-Like Growth Factor I Molecular Biology Genetics (clinical) Germ-Line Mutation Growth Disorders Mice Inbred ICR Kinase Growth factor Facies Natriuretic Peptide C-Type General Medicine Chondrogenesis Endochondral bone growth 0104 chemical sciences Failure to Thrive Disease Models Animal 030104 developmental biology Endocrinology Mutation |
Zdroj: | Human molecular genetics. 28(1) |
ISSN: | 1460-2083 |
Popis: | 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 BrafQ241R/+ 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 BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ 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 BrafQ241R/+ 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 BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome. |
Databáze: | OpenAIRE |
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