The dynactin subunit DCTN1 controls osteoclastogenesis via the Cdc42/PAK2 pathway
Open Access
- 24 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Experimental & Molecular Medicine
- Vol. 52 (3), 514-528
- https://doi.org/10.1038/s12276-020-0406-0
Abstract
Osteoclasts (OCs), cells specialized for bone resorption, are generated from monocyte/macrophage precursors by a differentiation process governed by RANKL. Here, we show that DCTN1, a key component of the dynactin complex, plays important roles in OC differentiation. The expression of DCTN1 was upregulated by RANKL. The inhibition of DCTN1 expression by gene knockdown suppressed OC formation, bone resorption, and the induction of NFATc1 and c-Fos, critical transcription factors for osteoclastogenesis. More importantly, the activation of Cdc42 by RANKL was inhibited upon DCTN1 silencing. The forced expression of constitutively active Cdc42 restored the OC differentiation of precursors with DCTN1 deletion. In addition, PAK2 was found to be activated by RANKL and to function downstream of Cdc42. The DCTN1-Cdc42 axis also inhibited apoptosis and caspase-3 activation. Furthermore, the anti-osteoclastogenic effect of DCTN1 knockdown was verified in an animal model of bone erosion. Intriguingly, DCTN1 overexpression was also detrimental to OC differentiation, suggesting that DCTN1 should be regulated at the appropriate level for effective osteoclastogenesis. Collectively, our results reveal that DCTN1 participates in the activation of Cdc42/PAK2 signaling and the inhibition of apoptosis during osteoclastogenesis.Keywords
Funding Information
- National Research Foundation of Korea (NRF-2017R1A2A1A17069648 and NRF-2018R1A5A2024418)
This publication has 49 references indexed in Scilit:
- Systematic dissection of dynein regulators in mitosisThe Journal of cell biology, 2013
- Disruption of the dynein-dynactin complex unveils motor-specific functions in osteoclast formation and bone resorptionJournal of Bone and Mineral Research, 2012
- Disruption of Kif3a in osteoblasts results in defective bone formation and osteopeniaJournal of Cell Science, 2012
- Signaling Role of Cdc42 in Regulating Mammalian PhysiologyOnline Journal of Public Health Informatics, 2011
- Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarizationJCI Insight, 2010
- Myosin X Regulates Sealing Zone Patterning in Osteoclasts through Linkage of Podosomes and MicrotubulesOnline Journal of Public Health Informatics, 2010
- Regulators of the cytoplasmic dynein motorNature Reviews Molecular Cell Biology, 2009
- p150/Glued Modifies Nuclear Estrogen Receptor FunctionMolecular Endocrinology, 2009
- RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in miceJCI Insight, 2008
- Dynactin Phosphorylation Is Modulated in Response to Cellular EffectorsBiochemical and Biophysical Research Communications, 1997