Spi-C positively regulates RANKL-mediated osteoclast differentiation and function

Exp Mol Med. 2020 Apr;52(4):691-701. doi: 10.1038/s12276-020-0427-8. Epub 2020 Apr 27.


Spi-C is an SPI-group erythroblast transformation-specific domain transcription factor expressed during B-cell development. Here, we report that Spi-C is a novel receptor activator of nuclear factor-κB ligand (RANKL)-inducible protein that positively regulates RANKL-mediated osteoclast differentiation and function. Knockdown of Spi-C decreased the expression of RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1, receptor activator of nuclear factor-κB (RANK), and tartrate-resistant acid phosphatase (TRAP), resulting in a marked decrease in the number of TRAP-positive multinucleated cells. Spi-C-transduced bone marrow-derived monocytes/macrophages (BMMs) displayed a significant increase in osteoclast formation in the presence of RANKL. In addition, Spi-C-depleted cells failed to show actin ring formation or bone resorption owing to a marked reduction in the expression of RANKL-mediated dendritic cell-specific transmembrane protein and the d2 isoform of vacuolar (H+) ATPase V0 domain, which are known osteoclast fusion-related genes. Interestingly, RANKL stimulation induced the translocation of Spi-C from the cytoplasm into the nucleus during osteoclastogenesis, which was specifically blocked by inhibitors of p38 mitogen-activated protein kinase (MAPK) or PI3 kinase. Moreover, Spi-C depletion prevented RANKL-induced MAPK activation and the degradation of inhibitor of κB-α (IκBα) in BMMs. Collectively, these results suggest that Spi-C is a novel positive regulator that promotes both osteoclast differentiation and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Bone Resorption
  • Cell Differentiation* / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Immunohistochemistry
  • Macrophages / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism*
  • Osteogenesis / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • RANK Ligand / metabolism*
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Biomarkers
  • DNA-Binding Proteins
  • RANK Ligand
  • RNA, Small Interfering
  • SPIC protein, human
  • p38 Mitogen-Activated Protein Kinases