The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase

Mócsai, Attila; Humphrey, Mary Beth; Ziffle, Jessica A. G. Van; Hu, Yongmei; Burghardt, Andrew J.; Spusta, Steven C.; Majumdar, Sharmila; Lanier, Lewis L.; Lowell, Clifford A.; Nakamura, Mary C.

doi:10.1073/pnas.0401602101

Cited by 431 publications

(487 citation statements)

References 34 publications

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“…The downstream intracellular signaling mediated by RANK in osteoclast progenitor cells includes TRAF6-dependent activation of nuclear factor (NF)-jB via the inhibitor of NF-jB (IjB) kinase (IKK)-IjB pathway and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK) (Boyle et al 2003;Lerner 2004;Teitelbaum and Ross 2003). In addition, immunoreceptor tyrosine-based activation motif-mediated costimulatory signals have been shown to be required for expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), the transcription factor believed to be crucial for osteoclast differentiation (Koga et al 2004;Mocasi et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of luteolin on osteoclast differentiation and function

et al. 2009

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Osteoclasts are multinucleated cells that play a crucial role in bone resorption, and are formed by the fusion of mononuclear osteoclasts derived from osteoclast precursors of the macrophage lineage. Compounds that specifically target functional osteoclasts would be ideal candidates for anti-resorptive agents for clinical applications. In the present study, we investigated the effects of luteolin, a flavonoid, on the regulation of receptor activator of nuclear factorjB ligand (RANKL)-induced osteoclastogenesis, functions and signaling pathway. Addition of luteolin to a coculture system of mouse bone marrow cells and ST2 cells in the presence of 10 -8 M 1a,25(OH) 2 D 3 caused significant inhibition of osteoclastogenesis. Luteolin had no effects on the 1a,25(OH) 2 D 3 -induced expressions of RANKL, osteoprotegerin and macrophage colony-stimulating factor mRNAs. Next, we examined the direct effects of luteolin on osteoclast precursors using bone marrow macrophages and RAW264.7 cells. Luteolin completely inhibited RANKL-induced osteoclast formation. Moreover, luteolin inhibited the bone resorption by mature osteoclasts accompanied by the disruption of their actin rings, and these effects were reversely induced by the disruption of the actin rings in mature osteoclasts. Finally, we found that luteolin inhibited RANKLinduced osteoclastogenesis through the suppression of ATF2, downstream of p38 MAPK and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) expression, respectively. Taken together, the present results indicate that naturally occurring luteolin has inhibitory activities toward both osteoclast differentiation and functions through inhibition of RANKL-induced signaling pathway as well as actin ring disruption, respectively.

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Section: Introductionmentioning

confidence: 99%

Inhibitory effect of luteolin on osteoclast differentiation and function

et al. 2009

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“…These adaptors associate with osteoclast-associated receptor (OSCAR), an immunoglobulin-like receptor [12][13][14]. Phosphorylation of ITAM-containing adaptors results in the recruitment of spleen tyrosine kinase (Syk), leading to the activation of PLCγ and subsequent calcium mobilization [10,12,13,15].…”

Section: Introductionmentioning

confidence: 99%

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

et al. 2013

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The receptor activator of NF-κB (RANK) and immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors are essential factors involved in regulating osteoclast formation and bone remodeling. Here, we identify early estrogen-induced gene 1 (EEIG1) as a novel RANK ligand (RANKL)-inducible protein that physically interacts with RANK and further associates with Gab2, PLCγ2 and Tec/Btk kinases upon RANKL stimulation. EEIG1 positively regulates RANKL-induced osteoclast formation, likely due to its ability to facilitate RANKL-stimulated PLCγ2 phosphorylation and NFATc1 induction. In addition, an inhibitory peptide designed to block RANK-EEIG1 interaction inhibited RANKL-induced bone destruction by reducing osteoclast formation. Together, our results identify EEIG1 as a novel RANK signaling component controlling RANK-mediated osteoclast formation, and suggest that targeting EEIG1 might represent a new therapeutic strategy for the treatment of pathological bone resorption.

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“…Osteoclast costimulation is an emerging concept that has recently come into acceptance based on the observation that combined deficiency of Fc receptor common ␥ subunit (FcR␥) and DNAX-activation protein 12 (DAP12) results in a complete lack of osteoclasts (4,5). In addition to receptor activator of NF-B (RANK), the receptor for RANK ligand (RANKL), the Ig-like receptors associated with FcR␥ and DAP12 have been recognized as essential receptors for osteoclastogenesis (2,3).…”

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confidence: 99%