The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

Matthew B. Greenblatt, Jae Hyuck Shim, Weiguo Zou, Despina Sitara, Michelle Schweitzer, Dorothy Hu, Sutada Lotinun, Yasuyo Sano, Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger Davis, Laurie H. Glimcher

Research output: Contribution to journalArticle

Abstract

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-β-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 p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.

Original languageEnglish (US)
Pages (from-to)2457-2473
Number of pages17
JournalJournal of Clinical Investigation
Volume120
Issue number7
DOIs
StatePublished - Jul 1 2010

ASJC Scopus subject areas

  • Medicine(all)

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    Greenblatt, M. B., Shim, J. H., Zou, W., Sitara, D., Schweitzer, M., Hu, D., Lotinun, S., Sano, Y., Baron, R., Park, J. M., Arthur, S., Xie, M., Schneider, M. D., Zhai, B., Gygi, S., Davis, R., & Glimcher, L. H. (2010). The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. Journal of Clinical Investigation, 120(7), 2457-2473. https://doi.org/10.1172/JCI42285