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La deleción de Ptpn11 en un nuevo progenitor causa metacondromatosis al inducir la señalización del erizo
Wentian Yang1, Jianguo Wang, Douglas C Moore
1Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA. wyang@lifespan.org
Nature
|July 19, 2013
Resumen
La tirosina fosfatasa SHP2 (codificada por PTPN11) actúa como un supresor de tumores en el cartílago, a diferencia de su papel en otras células. La pérdida de SHP2 en células progenitoras específicas causa metacondromatosis al interrumpir la señalización FGFR / MEK / ERK.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología del desarrollo Biología del desarrollo.
- Genética La genética.
Sus antecedentes:
- La tirosina fosfatasa SHP2 (PTPN11) es crucial para la función celular, con mutaciones relacionadas con el síndrome de Noonan y los cánceres.
- Las mutaciones PTPN11 inactivantes se han asociado recientemente con metacondromatosis, un trastorno esquelético raro, pero su patogénesis no está clara.
Objetivo del estudio:
- Para investigar el papel de PTPN11 en la patogénesis de la metacondromatosis.
- Para identificar el tipo específico de células y las vías de señalización involucradas en las anomalías esqueléticas con deficiencia de PTPN11.
Principales métodos:
- Utilizó ratones knockout condicional (Ptpn11(fl)) con Cre recombinasa (LysMCre o CtskCre) para eliminar específicamente Ptpn11 en diferentes linajes celulares.
- Realizó el rastreo del linaje para identificar nuevas poblaciones de células progenitoras.
- Analizó vías de señalización que incluyen ERK, Ihh y Pthrp, y probó intervenciones terapéuticas con FGFR / MEK e inhibidores suavizados.
Principales resultados:
- Los ratones con Ptpn11 eliminado en las células que expresan cathepsina K (Ctsk) (CtskCre;Ptpn11(fl/fl)) exhibieron características similares a las de la metacondromatosis.
- Se identificó una nueva población de células progenitoras que expresan CtskCre en la ranura pericondrial de Ranvier.
- La deficiencia de Shp2 en estos progenitores condujo a una disminución de la activación de FGFR / MEK / ERK, un aumento de la expresión de Ihh / Pthrp y una proliferación excesiva, imitando la metacondromatosis.
- El tratamiento con inhibidores suavizados mejoró los fenotipos de metacondromatosis.
Conclusiones:
- PTPN11 funciona como un supresor tumoral en una nueva población de células progenitoras del cartílago.
- La vía FGFR/MEK/ERK es crítica en la regulación de la producción de Ihh en estos progenitores.
- Dirigirse a esta vía tiene un potencial terapéutico para la metacondromatosis.
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