Syk, c-Src, the αvβ3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption

Zou, Wei; Kitaura, Hideki; Reeve, Jennifer; Long, Fanxin; Tybulewicz, Victor L. J.; Shattil, Sanford J.; Ginsberg, Mark H.; Ross, F. Patrick; Teitelbaum, Steven L.

doi:10.1083/jcb.200611083

Cited by 256 publications

(315 citation statements)

References 32 publications

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“…RANKL-induced intracellular Ca 2þ oscillation requires the PI3K/ AKT signaling pathway (11,19,40) and RANKL activates PI3K/AKT through the TRAF6 and c-Src complex in osteoclastogenesis. (15,16) In our study, we verified that CADPE inhibited the RANKL-induced interaction between TRAF6 and c-Src, suppressed the phosphorylation of AKT, and abrogated the oscillation of Ca 2þ , suggesting that CADPE modulated the TRAF/c-Src/PI3K/Ca 2þ signaling pathway in osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways

Yang

et al. 2012

Journal of Bone and Mineral Research

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Receptor activator of NF-kB ligand (RANKL) stimulation leads to the activation of mitogen-activated protein kinase (MAPK)/AP-1 and Ca 2þ -nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) signaling pathways in osteoclastogenesis. Targeting these pathways has been an encouraging strategy for bone-related diseases, such as postmenopausal osteoporosis. In this study, we examined the effects of caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) on osteoclastogenesis. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, CADPE suppressed RANKL-induced osteoclast differentiation and actin-ring formation in a dose-dependent manner within non-growth inhibitory concentrations at the early stage, while CADPE had no effect on macrophage colony-stimulating factor (M-CSF)-induced proliferation and differentiation. At the molecular level, CADPE inhibited RANKL-induced phosphorylation of MAPKs, including extracellular signal-regulated kinases 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK), without significantly affecting the NF-kB signaling pathway. CADPE abrogated RANKL-induced activator protein 1 (AP-1)/FBJ murine osteosarcoma viral oncogene homolog (c-Fos) nuclear translocation and activation. Overexpression of c-Fos prevented the inhibition by CADPE of osteoclast differentiation. Furthermore, CADPE suppressed RANKL-induced the tumor necrosis factor receptor associated factor 6 (TRAF6) interaction with c-src tyrosine kinase (c-Src), blocked RANKL-induced the phosphorylation of protein kinase B (AKT), and inhibited RANKL-induced Ca 2þ oscillation. As a result, CADPE decreased osteoclastogenesis-related marker gene expression, including NFATc1, TRAP, cathepsin K, and c-Src. To test the effects of CADPE on osteoclast activity in vivo, we showed that CADPE prevented ovariectomyinduced bone loss by inhibiting osteoclast activity. Together, our data demonstrate that CADPE suppresses osteoclastogenesis and bone loss through inhibiting RANKL-induced MAPKs and Ca 2þ -NFATc1 signaling pathways. CADPE is a novel agent in the treatment of osteoclast-related diseases, such as osteoporosis. ß

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Section: Discussionmentioning

confidence: 99%

Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways

Yang

et al. 2012

Journal of Bone and Mineral Research

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“…Syk has also been shown to signal from GPVI, the collagen receptor on platelets, by recruitment to the associated ITAMbearing FcRc subunit [7], from the NKG2D receptor of NK cells, from the C-type lectin Dectin-1 on dendritic cells [8], and from integrins on neutrophils, macrophages and osteoclasts via FcRc and the related DAP12 proteins [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Redundant role for Zap70 in B cell development and activation

Fallah-Arani

Schweighoffer²,

Vanes³

et al. 2008

Eur J Immunol

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Expression of the Syk family tyrosine kinase Zap70 is strongly correlated with poor clinical outcome in chronic lymphocytic leukemia, the most common human leukemia characterized by B cell accumulation. The expression of Zap70 may reflect the specific cell of origin of the tumor or may contribute to pathology. Thus, the normal role of Zap70 in B cell physiology is of great interest. While initial studies reported that Zap70 expression in the mouse was limited to T and NK cells, more recent work has shown expression in early B cell progenitors and in splenic B cells, suggesting that the kinase may play a role in the development or activation of B cells. In this study, we show that Zap70 is expressed in all developing subsets of B cells as well as in recirculating B cells, marginal zone B cells and peritoneal B1 cells. Analysis of Zap70-deficient mice shows no unique role for Zap70 in either the development of B cells or in their in vitro and in vivo activation. However, we show that Zap70 can rescue the defective positive selection of immature B cells into the recirculating pool in Syk-deficient mice, demonstrating functional redundancy between these two kinases.

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“…Integrin αvß3 is essential during osteoclast differentiation, most likely by controlling precursor migration and adhesion (Boissy et al, 1998, Kim et al, 2007, McHugh et al, 2000, Miyamoto et al, 2000. It is also necessary for osteoclast bone resorbing activity (Zou et al, 2007). Integrin αvß3 interaction with extracellular matrix proteins activates multiple signaling pathways, in particular phosphorylation cascades triggered by the tyrosine kinases Src and Pyk2 (Lakkakorpi et al, 2003, Miyazaki et al, 2004, to regulate podosome dynamics and organization, sealing zone formation and bone resorption (Destaing et al, 2008, Gil-Henn et al, 2007, Shyu et al, 2007.…”

Section: Introductionmentioning

confidence: 99%

The Rho GTPase Wrch1 regulates osteoclast precursor adhesion and migration

Brazier

Pawlak

Vives

et al. 2009

The International Journal of Biochemistry & Cell Biology

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Syk, c-Src, the αvβ3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption

Cited by 256 publications

References 32 publications

Redundant role for Zap70 in B cell development and activation

The Rho GTPase Wrch1 regulates osteoclast precursor adhesion and migration

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