The tyrosine kinase inhibitor GNF-2 suppresses osteoclast formation and activity

Kim, Hyun-Ju; Yoon, Hye‐Jin; Choi, Je‐Yong; Lee, Inkyu; Kim, Shin‐Yoon

doi:10.1189/jlb.0713356

Cited by 15 publications

(13 citation statements)

References 40 publications

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“…In fact, we found that capric acid blocked the actin ring re-formation induced by two cytokines, RANKL and MCSF, establishing that capric acid regulates the osteoclast cytoskeleton. These results are consistent with our previous findings that showed that defective cell spreading is accompanied by failure in osteoclast cytoskeleton organization (Hong et al, 2011; Kim et al, 2006; 2014a; 2014b). In addition, capric acid attenuated the expression of the β3 integrin subunit.…”

Section: Discussionsupporting

confidence: 94%

A Medium-Chain Fatty Acid, Capric Acid, Inhibits RANKL-Induced Osteoclast Differentiation via the Suppression of NF-κB Signaling and Blocks Cytoskeletal Organization and Survival in Mature Osteoclasts

Kim¹,

Yoon²,

Kim³

et al. 2014

Molecules and Cells

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Fatty acids, important components of a normal diet, have been reported to play a role in bone metabolism. Osteoclasts are bone-resorbing cells that are responsible for many bone-destructive diseases such as osteoporosis. In this study, we investigated the impact of a medium-chain fatty acid, capric acid, on the osteoclast differentiation, function, and survival induced by receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (MCSF). Capric acid inhibited RANKL-mediated osteoclastogenesis in bone marrow-derived macrophages and suppressed RANKL-induced IκBα phosphorylation, p65 nuclear translocation, and NF-κB transcriptional activity. Capric acid further blocked the RANKL-stimulated activation of ERK without affecting JNK or p38. The induction of NFATc1 in response to RANKL was also attenuated by capric acid. In addition, capric acid abrogated M-CSF and RANKL-mediated cytoskeleton reorganization, which is crucial for the efficient bone resorption of osteoclasts. Capric acid also increased apoptosis in mature osteoclasts through the induction of Bim expression and the suppression of ERK activation by M-CSF. Together, our results reveal that capric acid has inhibitory effects on osteoclast development. We therefore suggest that capric acid may have potential therapeutic implications for the treatment of bone resorption-associated disorders.

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Section: Discussionsupporting

confidence: 94%

A Medium-Chain Fatty Acid, Capric Acid, Inhibits RANKL-Induced Osteoclast Differentiation via the Suppression of NF-κB Signaling and Blocks Cytoskeletal Organization and Survival in Mature Osteoclasts

Kim¹,

Yoon²,

Kim³

et al. 2014

Molecules and Cells

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“…Previous work has demonstrated a role for Abl in OC formation by regulating the phosphorylation of c‐Fms and the downstream effector molecules Erk and Akt . Conversely, GNF‐2, an inhibitor of Abl, suppressed M‐CSF‐dependent activation of Erk and Akt, inhibited the proliferation and differentiation of OCs, interfered with actin cytoskeletal organization, and accelerated apoptosis of mature OCs . Consistent with these reports, we found the aforementioned biological processes to be significantly altered in RAW 264.7 cells compared with BMMs (Fig.…”

Section: Discussionsupporting

confidence: 90%

Comparative Characterization of Osteoclasts Derived From Murine Bone Marrow Macrophages and RAW 264.7 Cells Using Quantitative Proteomics

Ng¹,

Tu²,

Shen³

et al. 2018

JBMR Plus

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Osteoclasts are bone‐resorbing cells differentiated from macrophage/monocyte precursors in response to macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL). In vitro models are principally based on primary bone marrow macrophages (BMMs), but RAW 264.7 cells are frequently used because they are widely available, easy to culture, and more amenable to genetic manipulation than primary cells. Increasing evidence, however, has shown that the vastly different origins of these two cell types may have important effects on cell behavior. In particular, M‐CSF is a prerequisite for the differentiation of BMMs, by promoting survival and proliferation and priming the cells for RANKL induction. RAW 264.7 cells readily form osteoclasts in the presence of RANKL, but M‐CSF is not required. Based on these key differences, we sought to understand their functional implications and how it might affect osteoclast differentiation and related signaling pathways. Using a robust and high‐throughput proteomics strategy, we quantified the global protein changes in osteoclasts derived from BMMs and RAW 264.7 cells at 1, 3, and 5 days of differentiation. Data are available via ProteomeXchange with the identifier PXD009610. Correlation analysis of the proteomes demonstrated low concordance between the two cell types (R2 ≈ 0.13). Bioinformatics analysis indicate that RANKL‐dependent signaling was intact in RAW 264.7 cells, but biological processes known to be dependent on M‐CSF were significantly different, including cell cycle control, cytoskeletal organization, and apoptosis. RAW 264.7 cells exhibited constitutive activation of Erk and Akt that was dependent on the activity of Abelson tyrosine kinase, and the timing of Erk and Akt activation was significantly different between BMMs and RAW 264.7 cells. Our findings provide the first evidence for major discrepancies between BMMs and RAW 264.7 cells, indicating that careful consideration is needed when using the RAW 264.7 cell line for studying M‐CSF‐dependent signaling and functions. © 2018 American Society for Bone and Mineral Research. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…Previous genetic and pharmacological studies have confirmed a key role of M-CSF/cFms in osteoclast development [9,[42][43][44]. Interestingly, in this study, we found that exogenous LCN2 attenuated c-Fms expression.…”

Section: Discussionsupporting

confidence: 65%

Lipocalin-2 inhibits osteoclast formation by suppressing the proliferation and differentiation of osteoclast lineage cells

Kim

Yoon

et al. 2015

Experimental Cell Research

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The tyrosine kinase inhibitor GNF-2 suppresses osteoclast formation and activity

Cited by 15 publications

References 40 publications

A Medium-Chain Fatty Acid, Capric Acid, Inhibits RANKL-Induced Osteoclast Differentiation via the Suppression of NF-κB Signaling and Blocks Cytoskeletal Organization and Survival in Mature Osteoclasts

A Medium-Chain Fatty Acid, Capric Acid, Inhibits RANKL-Induced Osteoclast Differentiation via the Suppression of NF-κB Signaling and Blocks Cytoskeletal Organization and Survival in Mature Osteoclasts

Comparative Characterization of Osteoclasts Derived From Murine Bone Marrow Macrophages and RAW 264.7 Cells Using Quantitative Proteomics

Lipocalin-2 inhibits osteoclast formation by suppressing the proliferation and differentiation of osteoclast lineage cells

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