The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice.
Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-beta-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38beta and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38beta agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.
Greenblatt
Matthew B
MB
Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Shim
Jae-Hyuck
JH
Zou
Weiguo
W
Sitara
Despina
D
Schweitzer
Michelle
M
Hu
Dorothy
D
Lotinun
Sutada
S
Sano
Yasuyo
Y
Baron
Roland
R
Park
Jin Mo
JM
Arthur
Simon
S
Xie
Min
M
Schneider
Michael D
MD
Zhai
Bo
B
Gygi
Steven
S
Davis
Roger
R
Glimcher
Laurie H
LH
D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D050882:CREB-Binding Protein; D020930:MAP Kinase Kinase Kinases; D048308:Mitogen-Activated Protein Kinase 14; D020929:Mitogen-Activated Protein Kinase Kinases; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C494363:CREBBP protein, human; C069937:MAP3K8 protein, human