Transcriptional regulation of osteoblasts.
The differentiation of osteoblasts from mesenchymal precursors requires a series of cell fate decisions controlled by a hierarchy of transcription factors. These include RUNX2, Osterix (OSX), ATF4 and a large number of nuclear coregulators. During bone development, initial RUNX2 expression coincides with the formation of mesenchymal condensations and precedes the branching of chondrogenic and osteogenic lineages. Given its central role in bone development, it is not surprising that RUNX2 is subject to a variety of controls. These include posttranslational modification, especially phosphorylation, and interactions with accessory nuclear factors. Specific examples of RUNX2 regulation to be reviewed include phosphorylation by the ERK/MAP kinase pathway and interactions with DLX5. RUNX2 is regulated via phosphorylation of critical serine residues in the proline/serine/threonine domain. In vivo, the transgenic expression of constitutively active MAP kinase in osteoblasts accelerated skeletal development, while a dominant-negative MAPK retarded development in a RUNX2-dependent manner. DLX5-RUNX2 complexes can be detected in osteoblasts and this interaction plays a critical role in maintaining osteoblast-specific expression of the bone sialoprotein gene. These studies allow us to begin understanding the complex mechanisms necessary to fine-tune bone formation as mesenchymal progenitors progress down the osteoblast lineage.
Franceschi
Renny T
RT
School of Dentistry, University of Michigan, Ann Arbor, Mich. 48109-1078, USA. rennyf@umich.edu
Ge
Chunxi
C
Xiao
Guozhi
G
Roca
Hernan
H
Jiang
Di
D
D000818:Animals; D001846:Bone Development; D001842:Bone and Bones / Q000002:abnormalities / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D058574:Integrin-Binding Sialoprotein; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012795:Sialoglycoproteins / Q000378:metabolism; D014158:Transcription, Genetic; D019076:Transgenes
D002843:Chromatin; D050659:Core Binding Factor Alpha 1 Subunit; C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D012795:Sialoglycoproteins; D048049:Extracellular Signal-Regulated MAP Kinases