Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts

doi:10.1016/S0006-291X(03)00695-8

Biochemical and Biophysical Research Communications

Volume 305, Issue 2, 30 May 2003, Pages 211-214

https://doi.org/10.1016/S0006-291X(03)00695-8 Get rights and content

Abstract

Receptor activator of nuclear factor kappa B (RANK) is a tumor necrosis factor receptor (TNFR) family protein that plays an important role in the regulation of bone and immune systems. Cellular responses to RANK ligand (RANKL) and the signal transduction pathways of RANK have been well characterized in osteoclasts and osteoclast precursor cells. RANKL induces the differentiation of osteoclast precursor cells and stimulates the resorption function and survival of mature osteoclasts. The RANK signaling mechanisms involved in these responses include the recruitment of TNF receptor-associated factor proteins, the activation of transcription factors (NF-κB, AP-1, and NFAT2), the cascades of mitogen-activated protein kinases (ERK, JNK, and p38), and the induction of Src- and phosphatidylinositol 3-kinase-dependent Akt activation. Despite the identification of several molecular targets, a comprehensive understanding of RANK signaling requires further studies on more complicated issues such as the temporal and spatial pattern of the engagement of signaling molecules and the precise relationship between the signaling pathway and the cellular response.

Section snippets

TRAF adaptor proteins in RANK signaling

RANK belongs to the tumor necrosis factor receptor (TNFR) superfamily. As for the other TNFR family members, the TNF receptor-associated factor (TRAF) adaptor proteins appear to play an important role in the initial event of the signal transduction pathway induced by RANK. TRAFs 1, 2, 3, 5, and 6 were shown to bind through the conserved TRAF domain to RANK in vitro and in transfected cells [5], [6]. Among the TRAF proteins, TRAF6 seems to be critical for RANK signaling in osteoclasts since a

RANK signaling and NF-κB activation

As denoted by its name, RANK is an integral receptor protein possessing a signaling capacity for the strong activation of the NF-κB transcription factor. NF-κB activity seems to be critical for osteoclast differentiation as shown by the block in osteoclastogenesis in mice deficient in NF-κB proteins p50 and p52 [11]. NF-κB is retained in the cytoplasm as a complex with the inhibitory κB (IκB) protein in unstimulated cells. Stimuli that activate NF-κB induce the activation of IκB kinases (IKK),

RANK signaling via MAPK cascades

The activation of mitogen-activated protein kinases (MAPKs) through RANK signaling has been relatively well characterized. It has been demonstrated that members of all three MAPK families, ERK, JNK, and p38, were activated by RANK in osteoclasts or osteoclast precursors [12], [21], [22], [23]. Additionally, studies with p38 inhibitors have corroborated the involvement of p38 MAPK in osteoclastogenesis [21], [23]. Spleen cells derived from TRAF6-deficient mice failed to activate JNK and p38 in

RANK signaling through the PI3K/Akt pathway

The serine/threonine kinase Akt mediates, through the activation of multiple targets, the anti-apoptotic function of phosphatidylinositol 3-kinase (PI3K) in a variety of cell types [31]. In osteoclasts, RANK induced the activation of Akt, which was blocked by the PI3K inhibitor LY294002 [21], [22]. Furthermore, LY294002 reduced the RANK-mediated survival response of osteoclasts [22]. The PI3K inhibitor also displayed a potent inhibitory effect on osteoclast differentiation [21], which may have

Other molecules involved in RANK signaling

Recently, RANKL was shown to cause an induction and activation of NFAT2 during osteoclast differentiation in a manner dependent on TRAF6, c-Fos, and Ca²⁺-calcineurin [35]. Many of the RANK signaling pathways demonstrated in osteoclasts or osteoclast precursor cells also seem to be present in dendritic cells. However, RANK may engage signaling molecules in a unique way depending on the cell type. For example, RANK stimulated the nuclear translocation of C/EBPβ and the induction of its responsive

Future exploration of the RANK signaling pathways

Although several molecules have already been identified, additional kinases, phosphatases, scaffold proteins, and transcription factors are expected to be involved as mediators and effectors in RANK signaling. Along with efforts to find new molecules playing a role in RANK signaling, the pattern of the engagement of each signaling molecule should be of interest. Different patterns related to the activation of catalytic components and transcription factors, protein–protein interactions between

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Breakthroughs and ViewsSignal transduction by receptor activator of nuclear factor kappa B in osteoclasts

Abstract

Section snippets

TRAF adaptor proteins in RANK signaling

RANK signaling and NF-κB activation

RANK signaling via MAPK cascades

RANK signaling through the PI3K/Akt pathway

Other molecules involved in RANK signaling

Future exploration of the RANK signaling pathways

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Bone

Mol. Cell

J. Biol. Chem.

Trends Biochem. Sci.

J. Biol. Chem.

J. Biol. Chem.

Dev. Cell

J. Biol. Chem.

J. Biol. Chem.

Genes Dev.

Nature

Annu. Rev. Immunol.

Genes Cells

Proc. Natl. Acad. Sci. USA

Breakthroughs and Views
Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts