title: The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Rodríguez-Carballo
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gámez
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Sedó-Cabezón
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sánchez-Feutrie
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Manzanares-Céspedes
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Rosa
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Ventura
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000002:abnormalities; D005269:Femur / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D055786:Gene Knockout Techniques; D006706:Homeostasis; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D012886:Skull / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism
chemical_list: D048308:Mitogen-Activated Protein Kinase 14