Send to

Choose Destination
Mol Cells. 2017 Oct;40(10):706-713. doi: 10.14348/molcells.2017.0225. Epub 2017 Oct 17.

Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation.

Author information

Department of Life Science, Ewha Womans University, Seoul 03760, Korea.
The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Korea.
Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Korea.


Osteoclasts are bone-resorbing cells that are derived from hematopoietic precursor cells and require macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL) for their survival, proliferation, differentiation, and activation. The binding of RANKL to its receptor RANK triggers osteoclast precursors to differentiate into osteoclasts. This process depends on RANKL-RANK signaling, which is temporally regulated by various adaptor proteins and kinases. Here we summarize the current understanding of the mechanisms that regulate RANK signaling during osteoclastogenesis. In the early stage, RANK signaling is mediated by recruiting adaptor molecules such as tumor necrosis factor receptor-associated factor 6 (TRAF6), which leads to the activation of mitogen-activated protein kinases (MAPKs), and the transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Activated NF-κB induces the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the key osteoclastogenesis regulator. In the intermediate stage of signaling, the co-stimulatory signal induces Ca2+ oscillation via activated phospholipase Cγ2 (PLCγ2) together with c-Fos/AP-1, wherein Ca2+ signaling facilitates the robust production of NFATc1. In the late stage of osteoclastogenesis, NFATc1 translocates into the nucleus where it induces numerous osteoclast-specific target genes that are responsible for cell fusion and function.


nuclear factor of activated T-cells cytoplasmic 1; nuclear factor-κB; osteoclasts; receptor activator of nuclear factor-κB; tumor necrosis factor receptor-associated factors

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Publishing M2Community Icon for PubMed Central
Loading ...
Support Center