Related Experiment Video
Updated: Apr 19, 2026
Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
Osteopetrosis in TAK1-deficient mice owing to defective NF-κB and NOTCH signaling
Gaurav Swarnkar1, Kannan Karuppaiah1, Gabriel Mbalaviele2
1Department of Orthopaedic Surgery and Cell Biology & Physiology and.
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.
Insights
TGFβ-activated kinase (TAK1) regulates bone formation by controlling osteoclastogenesis. TAK1 deficiency increases NUMBL, inhibiting osteoclast formation, while NF-κB activation rescues this process.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- TGFβ-activated kinase (TAK1) is vital for cellular functions, but its complete mechanisms remain unclear.
- Osteoclastogenesis is crucial for bone remodeling, and its dysregulation leads to bone diseases like osteopetrosis.
Purpose of the Study:
- To elucidate the role of TAK1 in myeloid cells and its impact on osteoclastogenesis.
- To identify downstream pathways regulated by TAK1 in the context of bone metabolism.
Main Methods:
- Ablation of Tak1 in myeloid cells of mice.
- Analysis of osteoclastogenesis and bone phenotypes.
- Investigation of NUMB-like (NUMBL), Notch intracellular domain (NICD), and RBPJ signaling pathways.
- Assessment of NF-κB activation via IKK2.
Main Results:
- Tak1 ablation in myeloid cells led to osteopetrosis due to defective osteoclastogenesis.
- Tak1 deficiency increased NUMBL levels, inhibiting osteoclastogenesis.
- NUMBL regulated Notch signaling by degrading NICD, affecting RBPJ.
- Deletion of Rbpj partially rescued the osteopetrosis phenotype.
- NF-κB activation was essential for restoring osteoclastogenesis.
Conclusions:
- TAK1 integrates NF-κB activation and Notch/RBPJ signaling repression via NUMBL inhibition to regulate osteoclastogenesis in myeloid cells.
- This study reveals a novel mechanism for TAK1 in bone metabolism and osteoclast differentiation.
- Targeting the TAK1-NUMBL-Notch pathway could offer therapeutic strategies for bone disorders.
Related Concept Videos
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
02:26NF-kB-dependent Signaling Pathway