Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-ß/SMAD pathway.
J Exp Med
; 217(5)2020 05 04.
Article
en En
| MEDLINE
| ID: mdl-32232430
ABSTRACT
Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical "dripping candle wax" melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-ß pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-ß pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-ß/SMAD3 activation by BMP signaling in SMAD3 mutation-positive endosteal melorheostosis, which may guide future therapies.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Regulación hacia Arriba
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Factor de Crecimiento Transformador beta
/
Proteína smad3
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Melorreostosis
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Exp Med
Año:
2020
Tipo del documento:
Article
País de afiliación:
Moldova