Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development.
The extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) pathway provides a major link between the cell surface and nucleus to control proliferation and differentiation. However, its in vivo role in skeletal development is unknown. A transgenic approach was used to establish a role for this pathway in bone. MAPK stimulation achieved by selective expression of constitutively active MAPK/ERK1 (MEK-SP) in osteoblasts accelerated in vitro differentiation of calvarial cells, as well as in vivo bone development, whereas dominant-negative MEK1 was inhibitory. The involvement of the RUNX2 transcription factor in this response was established in two ways: (a) RUNX2 phosphorylation and transcriptional activity were elevated in calvarial osteoblasts from TgMek-sp mice and reduced in cells from TgMek-dn mice, and (b) crossing TgMek-sp mice with Runx2+/- animals partially rescued the hypomorphic clavicles and undemineralized calvaria associated with Runx2 haploinsufficiency, whereas TgMek-dn; Runx2+/- mice had a more severe skeletal phenotype. This work establishes an important in vivo function for the ERK-MAPK pathway in bone that involves stimulation of RUNX2 phosphorylation and transcriptional activity.
Ge
Chunxi
C
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Xiao
Guozhi
G
Jiang
Di
D
Franceschi
Renny T
RT
D000818:Animals; D030801:Animals, Genetically Modified; D001846:Bone Development; D002454:Cell Differentiation / Q000235:genetics; D002968:Clavicle / Q000033:anatomy & histology / Q000166:cytology / Q000201:enzymology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000201:enzymology; D010641:Phenotype; D010766:Phosphorylation; D012886:Skull / Q000033:anatomy & histology / Q000166:cytology / Q000201:enzymology; D014158:Transcription, Genetic; D019076:Transgenes
D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse