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


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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Available from: Juan Jaen, Oct 29, 2015
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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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    • "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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    • "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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