title: Biomechanical stimulation of osteoblast gene expression requires phosphorylation of the RUNX2 transcription factor.
abstract: Bone can adapt its structure in response to mechanical stimuli. At the cellular level, this involves changes in chromatin organization, gene expression, and differentiation, but the underlying mechanisms are poorly understood. Here we report on the involvement of RUNX2, a bone-related transcription factor, in this process. Fluid flow shear stress loading of preosteoblasts stimulated translocation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) to the nucleus where it phosphorylated RUNX2 on the chromatin of target genes, and increased histone acetylation and gene expression. MAPK signaling and two RUNX2 phosphoacceptor sites, S301 and S319, were critical for this response. Similarly, in vivo loading of mouse ulnae dramatically increased ERK and RUNX2 phosphorylation as well as expression of osteoblast-related genes. These findings establish ERK/MAPK-mediated phosphorylation of RUNX2 as a critical step in the response of preosteoblasts to dynamic loading and define a novel mechanism to explain how mechanical signals induce gene expression in bone.
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Chunxi
authors.initials: C
authors.lastname: Ge
authors.forename: Jason P
authors.initials: JP
authors.lastname: Long
authors.forename: Dana L
authors.initials: DL
authors.lastname: Begun
authors.forename: Jose A
authors.initials: JA
authors.lastname: Rodriguez
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldstein
authors.forename: Renny T
authors.initials: RT
authors.lastname: Franceschi
mesh_terms: D000107:Acetylation; D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D012212:Rheology; D013314:Stress, Mechanical; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D050659:Core Binding Factor Alpha 1 Subunit; D006657:Histones; C493716:Runx2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases