The dynactin subunit DCTN1 controls osteoclastogenesis via the Cdc42/PAK2 pathway

Exp Mol Med. 2020 Mar;52(3):514-528. doi: 10.1038/s12276-020-0406-0. Epub 2020 Mar 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Bone Resorption / metabolism
  • Caspase 3 / metabolism
  • Cell Differentiation / physiology
  • Disease Models, Animal
  • Dynactin Complex / metabolism*
  • Female
  • Macrophages / metabolism
  • Macrophages / physiology
  • Mice
  • Mice, Inbred ICR
  • NFATC Transcription Factors / metabolism
  • Osteoclasts / metabolism*
  • Osteoclasts / physiology
  • Osteogenesis / physiology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • RANK Ligand / metabolism
  • Signal Transduction / physiology*
  • Up-Regulation / physiology
  • cdc42 GTP-Binding Protein / metabolism*
  • p21-Activated Kinases / metabolism*


  • Cdc42 protein, mouse
  • Dctn1 protein, mouse
  • Dynactin Complex
  • NFATC Transcription Factors
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Pak2 protein, mouse
  • p21-Activated Kinases
  • Caspase 3
  • cdc42 GTP-Binding Protein