Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome.
Bone
; 73: 111-9, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25543012
ABSTRACT
Multiple synostoses syndrome 2 (SYNS2) is a rare genetic disease characterized by multiple fusions of the joints of the extremities, like phalangeal joints, carpal and tarsal joints or the knee and elbows. SYNS2 is caused by point mutations in the Growth and Differentiation Factor 5 (GDF5), which plays an essential role during skeletal development and regeneration. We selected one of the SYNS2-causing GDF5 mutations, p.N445T, which is known to destabilize the interaction with the Bone Morphogenetic Protein (BMP) antagonist NOGGIN (NOG), in order to generate the superagonistic GDF5 variant GDF5(N445T). In this study, we tested its capacity to support regeneration in a rat critical-sized defect model in vivo. MicroCT and histological analyses indicate that GDF5(N445T)-treated defects show faster and more efficient healing compared to GDF5 wild type (GDF5(wt))-treated defects. Microarray-based gene expression and quantitative PCR analyses from callus tissue point to a specific acceleration of the early phases of bone healing, comprising the inflammation and chondrogenesis phase. These results support the concept that disease-deduced growth factor variants are promising lead structures for novel therapeutics with improved clinical activities.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Sinostose
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Cicatrização
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Fator 5 de Diferenciação de Crescimento
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Bone
Assunto da revista:
METABOLISMO
/
ORTOPEDIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Alemanha