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The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice

BACKGROUND: p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 si...

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Autores principales: Rodríguez-Carballo, Edgardo, Gámez, Beatriz, Sedó-Cabezón, Lara, Sánchez-Feutrie, Manuela, Zorzano, Antonio, Manzanares-Céspedes, Cristina, Rosa, José Luis, Ventura, Francesc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090229/
https://www.ncbi.nlm.nih.gov/pubmed/25007355
http://dx.doi.org/10.1371/journal.pone.0102032
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author Rodríguez-Carballo, Edgardo
Gámez, Beatriz
Sedó-Cabezón, Lara
Sánchez-Feutrie, Manuela
Zorzano, Antonio
Manzanares-Céspedes, Cristina
Rosa, José Luis
Ventura, Francesc
author_facet Rodríguez-Carballo, Edgardo
Gámez, Beatriz
Sedó-Cabezón, Lara
Sánchez-Feutrie, Manuela
Zorzano, Antonio
Manzanares-Céspedes, Cristina
Rosa, José Luis
Ventura, Francesc
author_sort Rodríguez-Carballo, Edgardo
collection PubMed
description BACKGROUND: p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. CONCLUSIONS: Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.
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spelling pubmed-40902292014-07-14 The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice Rodríguez-Carballo, Edgardo Gámez, Beatriz Sedó-Cabezón, Lara Sánchez-Feutrie, Manuela Zorzano, Antonio Manzanares-Céspedes, Cristina Rosa, José Luis Ventura, Francesc PLoS One Research Article BACKGROUND: p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. CONCLUSIONS: Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects. Public Library of Science 2014-07-09 /pmc/articles/PMC4090229/ /pubmed/25007355 http://dx.doi.org/10.1371/journal.pone.0102032 Text en © 2014 Rodriguez-Carballo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Rodríguez-Carballo, Edgardo
Gámez, Beatriz
Sedó-Cabezón, Lara
Sánchez-Feutrie, Manuela
Zorzano, Antonio
Manzanares-Céspedes, Cristina
Rosa, José Luis
Ventura, Francesc
The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice
title The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice
title_full The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice
title_fullStr The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice
title_full_unstemmed The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice
title_short The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice
title_sort p38α mapk function in osteoprecursors is required for bone formation and bone homeostasis in adult mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090229/
https://www.ncbi.nlm.nih.gov/pubmed/25007355
http://dx.doi.org/10.1371/journal.pone.0102032
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