CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease

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Blood (Impact Factor: 10.45). 05/2012; 120(7):1449-57. DOI: 10.1182/blood-2011-10-384784
Source: PubMed

ABSTRACT The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.

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    • "Inhibition of CCR1 and CCR5 receptors by antagonists or neutralizing antibodies partially reduce osteoclastogenesis, osteolytic lesions, and MM-induced angiogenesis [34, 35, 42]. Recently, Dairaghi et al. [46] demonstrated that CCR1 blockade by the selective antagonist CCX721 reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease, likely by inhibiting the cross-talk of MM cells with OCs and OC precursors [46]. Thus the development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease is a further therapeutic possibility. "
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    ABSTRACT: Until recently, inflammatory chemokines were viewed mainly as indispensable "gate keepers" of immunity and inflammation. However, updated research indicates that cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. The CCR5 and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, but extensive studies on the role of the CCL5/CCR axis were performed only in a limited number of cancers. This review summarizes updated information on the role of CCL5 and its receptor CCR5 in cancer cell proliferation, metastasis, and the formation of an immunosuppressive microenvironment and highlights the development of newer therapeutic strategies aimed to inhibit the binding of CCL5 to CCR5, to inhibit CCL5 secretion, or to inhibit the interactions among tumor cells and the microenvironment leading to CCL5 secretion.
    Mediators of Inflammation 01/2014; 2014(8):292376. DOI:10.1155/2014/292376 · 3.24 Impact Factor
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    • "The participation of other axes of chemokines– chemokine receptors such as CCL2-CCR2 axis (Kim et al., 2006; Li et al., 2007; Binder et al., 2009), CCL5-CCR5 axis (Oba et al., 2005; Menu et al., 2006; Hoshino et al., 2009), and CX3CL1-CX3CR1 axis (Saitoh et al., 2007; Koizumi et al., 2009; Hoshino et al., 2013) also play roles in bone remodeling. Nowadays, some types of chemokines are responsible for pathological bone destruction through the regulation of osteoclasts and their precursor cells that are derived from common progenitor cells in bone marrow, thus suggesting that several chemokine antagonists provide a strong rationale for further development of the therapeutic targets of associated osteolytic bone disease such as multiple myeloma and rheumatoid arthritis (Oba et al., 2005; Menu et al., 2006; Dairaghi et al., 2012). These findings are referenced in favor of therapeutic treatments targeting chemokines to prevent pathogenic bone resorption. "
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    ABSTRACT: Spinal tuberculosis is a condition characterized by massive resorption of the spinal vertebrae due to the infection with Mycobacterium tuberculosis (Mtb). However, the pathogenesis of spinal tuberculosis has not been established, because spinal tuberculosis has almost been completely eradicated by the establishment of antibiotic treatment in the mid-20th century. In this study, we investigated the inflammatory responses of human multinucleated osteoclasts infected with virulent Mtb strain. We found that the intracellular Mtb infection of multinuclear osteoclasts resulted in the rapid growth of Mtb and an osteolytic response, rather than inflammation. In response to Mtb infection, the mononuclear osteoclast precursors produced proinflammatory cytokines including TNF-α, which was an intrinsic characteristic they have in common with macrophages. In contrast, highly-fused multinucleated osteoclasts incapacitated the production of these cytokines. Instead, the intracellular Mtb inside multinuclear osteoclasts was escaped from the endosome/phagosome, and lead to different pattern of osteoclast activation with the production of chemokines such as CCL5, CCL17, CCL20, CCL22, CCL24 and CCL25. Moreover, intracellular infection with an avirulent Mtb strain resulted in the diminished production of these chemokines. Taken together, these findings indicate that intracellular Mtb infection in multinuclear osteoclasts reprograms osteoclast development via the dysregulation of cytokines and chemokines. This article is protected by copyright. All rights reserved.
    Pathogens and Disease 08/2013; 70(1). DOI:10.1111/2049-632X.12082 · 2.40 Impact Factor
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    • "The results suggest that the therapeutic regulation of CCR1 expression and function may be useful for controlling bone resorption. Consistent with our data, it was very recently reported that CCR1 blockade efficiently blocked osteolysis in a mouse model of myeloma bone disease [42]. We also found that a CCR1 ligand, MIP-1α, was chemotactic for preosteoclasts, and stimulated fusion. "
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    ABSTRACT: Osteoclasts are unique multinucleated cells formed by fusion of preosteoclasts derived from cells of the monocyte/macrophage lineage, which are induced by RANKL. However, characteristics and subpopulations of osteoclast precursor cells are poorly understood. We show here that a combination of TNF-α, TGF-β, and M-CSF efficiently generates mononuclear preosteoclasts but not multinucleated osteoclasts (MNCs) in rat bone marrow cultures depleted of stromal cells. Using a rat osteoclast-specific mAb, Kat1, we found that TNF-α and TGF-β specifically increased Kat1(+)c-fms(+) and Kat1(+)c-fms(-) cells but not Kat1(-)c-fms(+) cells. Kat1(-)c-fms(+) cells appeared in early stages of culture, but Kat1(+)c-fms(+) and Kat1(+)c-fms(-) cells increased later. Preosteoclasts induced by TNF-α, TGF-β, and M-CSF rapidly differentiated into osteoclasts in the presence of RANKL and hydroxyurea, an inhibitor of DNA synthesis, suggesting that preosteoclasts are terminally differentiated cells. We further analyzed the expression levels of genes encoding surface proteins in bone marrow macrophages (BMM), preosteoclasts, and MNCs. Preosteoclasts expressed itgam (CD11b) and chemokine receptors CCR1 and CCR2; however, in preosteoclasts the expression of chemokine receptors CCR1 and CCR2 was not up-regulated compared to their expression in BMM. However, addition of RANKL to preosteoclasts markedly increased the expression of CCR1. In contrast, expression of macrophage antigen emr-1 (F4/80) and chemokine receptor CCR5 was down-regulated in preosteoclasts. The combination of TNF-α, TGF-β, and M-CSF induced Kat1(+)CD11b(+) cells, but these cells were also induced by TNF-α alone. In addition, MIP-1α and MCP-1, which are ligands for CCR1 and CCR2, were chemotactic for preosteoclasts, and promoted multinucleation of preosteoclasts. Finally, we found that Kat1(+)c-fms(+) cells were present in bone tissues of rats with adjuvant arthritis. These data demonstrate that TNF-α in combination with TGF-β efficiently generates preosteoclasts in vitro. We delineated characteristics that are useful for identifying and isolating rat preosteoclasts, and found that CCR1 expression was regulated in the fusion step in osteoclastogenesis.
    PLoS ONE 10/2012; 7(10):e47930. DOI:10.1371/journal.pone.0047930 · 3.23 Impact Factor
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