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Research Article

Osteopetrosis in TAK1-deficient mice owing to defective NF-κB and NOTCH signaling

Gaurav Swarnkar, Kannan Karuppaiah, Gabriel Mbalaviele, Tim (Hung-Po) Chen, and Yousef Abu-Amer
PNAS January 6, 2015 112 (1) 154-159; first published December 22, 2014; https://doi.org/10.1073/pnas.1415213112
Gaurav Swarnkar
aDepartment of Orthopaedic Surgery and Cell Biology & Physiology and
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Kannan Karuppaiah
aDepartment of Orthopaedic Surgery and Cell Biology & Physiology and
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Gabriel Mbalaviele
bBone and Mineral Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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Tim (Hung-Po) Chen
aDepartment of Orthopaedic Surgery and Cell Biology & Physiology and
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Yousef Abu-Amer
aDepartment of Orthopaedic Surgery and Cell Biology & Physiology and
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  • For correspondence: abuamery@wustl.edu
  1. Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, and approved November 26, 2014 (received for review August 7, 2014)

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Significance

Skeletal anomalies are major health disparities resulting from dysregulation of bone homeostasis. Osteoclasts (OCs) are the principal bone resorbing and remodeling cells. The function of the OC relies on intricate signaling network dominated by NF-κB and MAP kinases. TGF-β activated kinase-1 (TAK1) is the proximal activator of these pathways and ultimately is a key target for regulating cellular functions. The role of TAK1 in physiologic and pathologic cellular functions has been widely described. However, the precise mechanism by which TAK1 regulates these functions remains enigmatic. We discovered a novel mechanism by which TAK1 regulates expression of the sensory proteins NUMB/NUMB-like and subsequent activation of Notch–recombinant recognition sequence binding protein at Jκ site (RBPJ) pathway in myeloid cells. We provide genetic evidence that dysregulation of this pathway leads to osteopetrosis.

Abstract

The MAP kinase TGFβ-activated kinase (TAK1) plays a crucial role in physiologic and pathologic cellular functions including cell survival, differentiation, apoptosis, inflammation, and oncogenesis. However, the entire repertoire of its mechanism of action has not been elucidated. Here, we found that ablation of Tak1 in myeloid cells causes osteopetrosis in mice as a result of defective osteoclastogenesis. Mechanistically, Tak1 deficiency correlated with increased NUMB-like (NUMBL) levels. Accordingly, forced expression of Numbl abrogated osteoclastogenesis whereas its deletion partially restored osteoclastogenesis and reversed the phenotype of Tak1 deficiency. Tak1 deletion also down-regulated Notch intracellular domain (NICD), but increased the levels of the transcription factor recombinant recognition sequence binding protein at Jκ site (RBPJ), consistent with NUMBL regulating notch signaling through degradation of NICD, a modulator of RBPJ. Accordingly, deletion of Rbpj partially corrected osteopetrosis in Tak1-deficient mice. Furthermore, expression of active IKK2 in RBPJ/TAK1-deficient cells significantly restored osteoclastogenesis, indicating that activation of NF-κB is essential for complete rescue of the pathway. Thus, we propose that TAK1 regulates osteoclastogenesis by integrating activation of NF-κB and derepression of NOTCH/RBPJ in myeloid cells through inhibition of NUMBL.

  • osteoclast
  • osteopetrosis
  • NUMBL
  • TAK1
  • RBPJ

Footnotes

  • ↵1G.S. and K.K. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: abuamery{at}wustl.edu.
  • Author contributions: Y.A.-A. designed research; G.S., K.K., and T.H.-P.C. performed research; G.M. contributed new reagents/analytic tools; G.S., K.K., G.M., and Y.A.-A. analyzed data; and G.S. and Y.A.-A. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1415213112/-/DCSupplemental.

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Deletion of TAK1 leads to osteopetrosis
Gaurav Swarnkar, Kannan Karuppaiah, Gabriel Mbalaviele, Tim (Hung-Po) Chen, Yousef Abu-Amer
Proceedings of the National Academy of Sciences Jan 2015, 112 (1) 154-159; DOI: 10.1073/pnas.1415213112

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Deletion of TAK1 leads to osteopetrosis
Gaurav Swarnkar, Kannan Karuppaiah, Gabriel Mbalaviele, Tim (Hung-Po) Chen, Yousef Abu-Amer
Proceedings of the National Academy of Sciences Jan 2015, 112 (1) 154-159; DOI: 10.1073/pnas.1415213112
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