Macrophage inflammatory protein‐1α induces osteoclast formation by activation of the MEK/ERK/c‐Fos pathway and inhibition of the p38MAPK/IRF‐3/IFN‐β pathway

Tsubaki, Masanobu; Kato, Chisato; Isono, Ai; Kaneko, Junichi; Isozaki, Misako; Satou, Takao; Itoh, Tatsuki; Kidera, Yasuhiro; Tanimori, Yoshihiro; Yanae, Masashi; Nishida, Shozo

doi:10.1002/jcb.22907

Cited by 28 publications

(20 citation statements)

References 25 publications

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“…We used C7 cells, which are mouse macrophage-like cells that have the ability to differentiate into osteoclasts [19,20]. The C7 cells were kindly provided by Dr. Shin-ichi Hayashi (Tottori University, Japan) and cultured in α-minimal essential medium (Sigma) supplemented with 10% fetal calf serum (Gibco, Carlsbad, CA), 50 ng/mL human recombinant M-CSF (Leukoprol; Kyowa Hakko, Shizuoka, Japan), 100 U/mL penicillin (Gibco) and 100 μg/mL streptomycin (Gibco), in an atmosphere containing 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation

et al. 2014

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BackgroundBisphosphonates are an important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Recent studies have shown that nitrogen-containing bisphosphonates induced apoptosis in rabbit osteoclasts and prevented prenylated small GTPase. However, whether bisphosphonates inhibit osteoclast formation has not been determined. In the present study, we investigated the inhibitory effect of minodronate and alendronate on the osteoclast formation and clarified the mechanism involved in a mouse macrophage-like cell lines C7 and RAW264.7.ResultsIt was found that minodronate and alendronate inhibited the osteoclast formation of C7 cells induced by receptor activator of NF-κB ligand and macrophage colony stimulating factor, which are inhibited by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. It was also found that minodronate and alendronate inhibited the osteoclast formation of RAW264.7 cells induced by receptor activator of NF-κB ligand. Furthermore, minodronate and alendornate decreased phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; similarly, U0126, a mitogen protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited osteoclast formation.ConclusionsThis indicates that minodronate and alendronate inhibit GGPP biosynthesis in the mevalonate pathway and then signal transduction in the MEK/ERK and PI3K/Akt pathways, thereby inhibiting osteoclast formation. These results suggest a novel effect of bisphosphonates that could be effective in the treatment of bone metabolic diseases, such as osteoporosis.

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Section: Methodsmentioning

confidence: 99%

Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation

et al. 2014

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“…Recently, it was reported that MIP1␣ (macrophage inflammatory protein 1␣) induces osteoclast formation by activating the MEK/ERK/c-Fos pathway (26) and that vitamin E inhibits RANKL-induced osteoclast differentiation from precursors by suppression of c-Fos expression, possibly through inhibiting ERK (27). To investigate the role of the ERK, JNK, and p38 pathways in the inhibitory effect of NMP, RAW264.7 cells were treated as indicated in Fig.…”

Section: Nmp Inhibits Nfatc1 and C-fos Expression And Decreases Ap-1 mentioning

confidence: 99%

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Ghayor

Correro

Lange

et al. 2011

Journal of Biological Chemistry

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Regulation of RANKL (receptor activator of nuclear factor B ligand)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. Osteoclasts are multinucleated cells that play a crucial role in bone resorption. In this study, we investigated the effects of N-methylpyrrolidone (NMP) on the regulation of RANKL-induced osteoclastogenesis. NMP inhibited RANKL-induced tartrate-resistant acid phosphatase activity and the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. The RANKL-induced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and c-Fos, which are key transcription factors for osteoclastogenesis, was also reduced by treatment with NMP. Furthermore, NMP induced disruption of the actin rings and decreased the mRNAs of cathepsin K and MMP-9 (matrix metalloproteinase-9), both involved in bone resorption. Taken together, these results suggest that NMP inhibits osteoclast differentiation and attenuates bone resorption. Therefore, NMP could prove useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption.Bone remodeling is a physiological process that involves the resorption and synthesis of bone by osteoclasts and osteoblasts, respectively (1, 2). Osteoclasts are known to be formed by the fusion of hematopoietic cells of the monocyte-macrophage lineage during the early stage of the differentiation process (3). This process consists of multiple steps, including differentiation of osteoclast precursors into mononuclear osteoclasts, fusion of mononuclear preosteoclasts into mature multinucleated osteoclasts, and activation of osteoclasts to resorb bone (4 -7). The terminal differentiation in this lineage is characterized by acquisition of mature phenotypic markers such as expression of tartrate-resistant acid phosphatase (TRAP), 2 the calcitonin receptor, MMP-9, and cathepsin K, as well as morphological conversion into large multinucleated cells and the ability to form resorption lacunae on bone (8 -10). The essential signaling molecules for osteoclast differentiation include RANKL and M-CSF (macrophage colony-stimulating factor) in bone marrow-derived macrophage precursor cells (11,12).RANKL is a member of the TNF superfamily that is expressed in osteoblasts. It interacts with the osteoclast cell surface receptor RANK, which in turn recruits TNF receptor-associated factors and plays a crucial role in the osteoclast differentiation axis (13,14). The downstream intracellular signaling mediated by RANK in osteoclast progenitor cells includes TRAF6 (TNF receptor-associated factor 6)-dependent activation of NF-B via the IB kinase complex and MAPKs such as ERK, p38 MAPK, and JNK (7,11,15). In addition, RANKL induces the key transcription factors for osteoclastogenesis, NFATc1 and c-Fos (9, 16, 17). Therefore, chemical or natural compounds that specifically inhibit these steps could be developed as antiresorptive drugs for the treatment of metabolic bone disorders characterized by e...

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“…MIP‐1α promotes cell growth and survival by binding to chemokine receptor 1 (CCR1) and CCR5, and activating ERK1/2 and Akt (Lentzsch et al, ; Tsubaki et al, , ). In the present study, we investigated the mechanism of enhanced cytotoxicity of melphalan with MIP‐1α neutralizing antibody.…”

Section: Discussionmentioning

confidence: 99%

The MIP‐1α autocrine loop contributes to decreased sensitivity to anticancer drugs

Tsubaki

Takeda

Tomonari

et al. 2017

Journal Cellular Physiology

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Several autocrine soluble factors, including macrophage inflammatory protein-1α (MIP-1α), tumor necrosis factor-α, and hepatocyte growth factor, promote cell survival and growth in multiple myeloma (MM) cells. We hypothesized that inhibition of the MIP-1α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, an MIP-1α neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of melphalan or bortezomib on MM cells. In addition, melphalan resistance cells (RPMI8226/L-PAM and HS-sultan/L-PAM cells) secreted MIP-1α and neutralizing antibody of MIP-1α partially overcame melphalan resistance. Moreover, combination treatment with MIP-1α neutralizing antibody and melphalan or bortezomib inhibited extracellular signal regulated kinase 1/2 (ERK1/2), Akt, and mammalian target of rapamycin (mTOR) activation, Bcl-2, Bcl-xL, and Survivin expression, and upregulated the expression of Bim and cleaved Poly (ADP-ribose) polymerase (PARP). Treatment of IM9 cells with MIP-1α siRNA suppressed the activation of ERK1/2, Akt, and mTOR, and enhanced the cytotoxic effect of melphalan and bortezomib. These results indicate that MIP-1α neutralizing antibodies or MIP-1α siRNA enhance the cytotoxic effect of melphalan and bortezomib by suppressing the chemokine receptor/ERK and chemokine receptor/Akt/mTOR pathways. The inhibition of MIP-1α may thus provide a new therapeutic approach to control tumor progression and bone destruction in patients with MM.

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Macrophage inflammatory protein‐1α induces osteoclast formation by activation of the MEK/ERK/c‐Fos pathway and inhibition of the p38MAPK/IRF‐3/IFN‐β pathway

Cited by 28 publications

References 25 publications

Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation

Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

The MIP‐1α autocrine loop contributes to decreased sensitivity to anticancer drugs

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