RESUMEN
p53 is a well known tumor suppressor. We show that p53 also regulates osteoblast differentiation, bone formation, and osteoblast-dependent osteoclast differentiation. Indeed, p53(-/-) mice display a high bone mass phenotype, and p53(-/-) osteoblasts show accelerated differentiation, secondary to an increase in expression of the osteoblast differentiation factor osterix, as a result. Reporter assays indicate that p53 represses osterix transcription by the minimal promoter in a DNA-binding-independent manner. In addition, p53(-/-) osteoblasts have an enhanced ability to favor osteoclast differentiation, in association with an increase in expression of macrophage-colony stimulating factor, which is under the control of osterix. Furthermore, inactivating p53 is sufficient to rescue the osteoblast differentiation defects observed in mice lacking c-Abl, a p53-interacting protein. Thus, these results identify p53 as a novel regulator of osteoblast differentiation, osteoblast-dependent osteoclastogenesis, and bone remodeling.
Asunto(s)
Remodelación Ósea/fisiología , Diferenciación Celular/fisiología , Osteoblastos/metabolismo , Osteoclastos/fisiología , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/fisiología , Animales , Diferenciación Celular/genética , Proliferación Celular , Células Cultivadas , Femenino , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Osteoblastos/citología , Osteoclastos/citología , Proteínas Proto-Oncogénicas c-abl/metabolismo , Factor de Transcripción Sp7 , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Regulación hacia ArribaRESUMEN
Template-induced hydroxyapatite (HA) has broad prospects in the applied fields of regenerative medicine and bone repair. HA thin coatings have been deposited on vertically aligned multiwalled carbon nanotubes (CNTs) via the high-temperature radio-frequency (rf) magnetron sputtering deposition technique. Simulated body fluid (SBF) solution has been used to soak and incubate the HA/CNTs nanocomposites at 37 degrees C. SEM, EDS, XRD, and FTIR characterizations revealed bonelike apatite formation on top of HA/CNTs composites. Coating HA material on well-aligned CNT-template provides a way of combining the superior mechanical properties and chemical stability of the CNTs with the excellent biochemical properties of HA.
Asunto(s)
Apatitas/química , Nanotubos de Carbono , Microscopía Electrónica de Rastreo , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Platelet-derived growth factors (PDGFs) play important roles in skeletal development and bone fracture healing, yet how PDGFs execute their functions remains incompletely understood. Here we show that PDGF-AA, but not -AB or -BB, could activate the BMP-Smad1/5/8 pathway in mesenchymal stem cells (MSCs), which requires BMPRIA as well as PDGFRα. PDGF-AA promotes MSC osteogenic differentiation through the BMP-Smad1/5/8-Runx2/Osx axis and MSC migration via the BMP-Smad1/5/8-Twist1/Atf4 axis. Mechanistic studies show that PDGF-AA activates BMP-Smad1/5/8 signaling by feedback down-regulating PDGFRα, which frees BMPRI and allows for BMPRI-BMPRII complex formation to activate smad1/5/8, using BMP molecules in the microenvironment. This study unravels a physical and functional interaction between PDGFRα and BMPRI, which plays an important role in MSC differentiation and migration, and establishes a link between PDGF-AA and BMPs pathways, two essential regulators of embryonic development and tissue homeostasis.
Asunto(s)
Proteína Morfogenética Ósea 2/metabolismo , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Smad/metabolismo , Animales , Western Blotting , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/deficiencia , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Osteogénesis/genética , Unión Proteica , Interferencia de ARN , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de Señal/efectos de los fármacos , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Proteína Smad8/metabolismoRESUMEN
Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1-Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16(INK4a). c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16(INK4a) upregulation and osteoblast senescence. Mouse genetic studies revealed that p16(INK4a) controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16(INK4a) expression and osteoprogenitor expansion.