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, 40 (10), 706-713

Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation


Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation

Jin Hee Park et al. Mol Cells.


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.

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


Fig. 1
Fig. 1. Initiation of RANK signaling is mediated by TRAF6
RANK stimulation by RANKL binding induces the recruitment and activation of a major adaptor protein, TRAF6. TRAF6 activates NF-κB either by interacting with p62 and aPKC or via TAK1 phosphorylation to regulate the IKK complex. Gab2 and PLCγ2 are other molecules that are required for NF-κB activation; they are recruited to RANK and activated. In addition, TRAF6 complexes with TAK1-TABs or TAK1-RACK1-MKK6 to facilitate the activation of MAPKs such as p38, JNK, and ERK. ROS produced by the RANK-TRAF6-Rac1-Nox1 cascades regulate MAPK activation. Activation of NF-κB and MAPKs leads to the induction of c-Fos at the initial stage of RANK signaling. RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand; TRAF6, TNF receptor-associated factors 6; NF-κB, nuclear factor-κB; aPCK, atypical protein kinase C; IKK, IκB kinase; TAK1, TGFβ-activated kinase 1; Gab2, growth factor receptor-bound protein 2 (Grb2)-associated binder-2; PLCγ2, phospholipase Cγ2; TAB, TAK1-binding protein; RACK1, receptor for activated C kinase 1; MAPKs, mitogen-activated protein kinases; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; ROS, reactive oxygen species; NOX1, NADPH oxidase 1; AP-1, activator protein-1; NFATc1, nuclear factor of activated T-cells cytoplasmic 1.
Fig. 2
Fig. 2. Cooperation of RANK signaling with costimulatory receptors
RANK signaling cooperates with immunoglobulin-like receptor/ITAM signals such as TREM-2/DAP12 and OSCAR/FcRγ, thereby leading to the amplification and translocation of NFATc1. When ITAM is tyrosine phosphorylated, Btk/Tec and BLNK/SLP-76 form a complex with PLCγ2 to activate PLCγ2 and Ca2+ signaling. EEIG1 induced by NFATc1 associates with Gab2 via the IVVY motif in RANK and then activates Btk/Tec followed by PLCγ2, suggesting that EEIG1 integrates RANK and ITAM signaling. Ca2+ oscillation induces calmodulin and calcineurin activation to regulate the nuclear translocation and amplification of NFATc1. The subcellular localization of NFATc1 is influenced by the phosphorylation of serine residues regulated by Gsk-3β, which is inhibited by either PI3K-Akt signaling or PKCβ. ITAM, immunoreceptor tyrosine-based activation motif; TREM-2, triggering receptor expressed in myeloid cells-2; DAP12, DNAX-activation protein 12; OSCAR, osteoclast-associated receptor; FcRγ, Fc receptor common γ subunit; Btk, Bruton’s tyrosine kinase; BLNK, B cell linker protein; SLP-76, Src homology 2 domain-containing leukocyte protein of 76 kD; EEIG1, early estrogen-induced gene 1; Gsk-3β, Glycogen synthase kinase-3β; PI3K, phosphoinositide 3-kinase; PKCβ, protein kinase Cβ.
Fig. 3
Fig. 3. Late stage of RANK signaling
Amplified NFATc1 induces its target genes to regulate osteoclast differentiation, cell fusion, and function. NFATc1 represses negative regulators such as MafB, IRF-8, and Bcl6 during osteoclast differentiation by inducing Blimp1 and Sirt6, which act as transcription repressors. In addition, NFATc1 cooperates with other transcription factors such as MITF, c-Fos, and PU.1 to regulate osteoclast fusion by inducing DC-STAMP, Atp6v0d2, and Tks5. The αVβ3 integrin signal activates c-Src by binding to vitronectin. Next, c-Src phosphorylates Syk, which recruits DAP12 and SLP-76 to form a complex with Vav3. This complex activates Rac1 or Cdc42 and regulates the cytoskeleton organization that is important for regulating bone resorption. MafB, v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B; IRF-8, interferon regulatory factor-8; Bcl6, B cell lymphoma 6; Blimp1, B-lymphocyte-induced maturation protein 1; Sirt6, sirtuin 6; MITF, microphthalmia-associated transcription factor; DC-STAMP, dendritic-cell-specific transmembrane protein; TRAP, tartrate-resistant acid phosphatase; Cdc42, cell division cycle 42.

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