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A Tak1/p38 Signaling Axis Regulates Runx2 Activity and Osteoblast Functions

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Osteoimmunology

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Abstract

Mitogen-activated protein kinases (MAPKs) are evolutionarily ancient signal transduction pathways well-studied as mediators of a variety of immunological responses. Despite the involvement of MAPKs in signal transduction downstream of various growth factors relevant to osteoblasts, the exact role of MAPKs in osteoblasts remains poorly understood. We have examined in particular the role of an MAP3K, TGFβ-activated kinase 1 (TAK1/MAP3K7), finding that mice with a conditional deletion of Tak1 in ostoeblasts display severe osteopenia and stigmata of human cleidocranial dysplasia, a skeletal disorder caused by haploinsufficency for the master regulator of osteoblast differentiation, Runx2. Examination of pathways downstream of TAK1 demonstrates that p38α and p38β mediate phosphorylation and activation of Runx2 by promoting the interaction between Runx2 and cofactor CBP. Thus, the p38 pathway is a critical regulator of Runx2 activity, connecting growth factor signaling to osteoblast differentiation.

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Acknowledgments

We gratefully acknowledge the support of our collaborators in this study: Drs. Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger Davis, and Dorothy Hu, Sutada Lotinun, Yasuyo Sano, and Judy Reilly. This work was funded by NIH grant HD055601 (LHG).

LHG is a member of the board of directors of and holds equity in Bristol-Myers Squibb.

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Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA

    Matthew B. Greenblatt, Jae-Hyuck Shim, Weiguo Zou & Laurie H. Glimcher

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  1. Matthew B. Greenblatt
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  2. Jae-Hyuck Shim
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  3. Weiguo Zou
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  4. Laurie H. Glimcher
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Corresponding author

Correspondence to Laurie H. Glimcher .

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Editors and Affiliations

  1. School of Medicine, Dept. Pathology & Lab. Medicine, University of Pennsylvania, Curie Blvd., Philadelphia, 19104, Pennsylvania, USA

    Yongwon Choi

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Greenblatt, M.B., Shim, JH., Zou, W., Glimcher, L.H. (2013). A Tak1/p38 Signaling Axis Regulates Runx2 Activity and Osteoblast Functions. In: Choi, Y. (eds) Osteoimmunology. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5366-6_6

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