Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease

University of Texas at San Antonio, San Antonio, Texas, United States
Blood (Impact Factor: 10.45). 08/2003; 102(1):311-9. DOI: 10.1182/blood-2002-12-3905
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Recent data have implicated macrophage inflammatory protein-1alpha (MIP-1alpha) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1alpha requires other factors such as receptor activator of nuclear factor-kappaB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1alpha antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1alpha on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1alpha (CHO/MIP-1alpha) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1alpha tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1alpha tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1alpha tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1alpha over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1alpha had no effect in RANK-/- mice. Together, these results establish that MIP-1alpha is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1alpha exerts a dual effect in myeloma, on osteoclasts, and tumor cells.

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    • "Animal protocols were approved by the Mayo Clinic Institutional Care and Use Committee. Female C57BL/KaLwRijHsd mice were obtained from Harlan Laboratories (Netherlands), and syngeneic murine myeloma 5TGM1 cells were implanted.33 For subcutaneous studies, 5×106 5TGM1 cells were implanted, and VSV (108 TCID50) was administered intravenously (IV; via the tail vein) 14 days later. "
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    • "Bone marrow cells were flushed from the bone cavity of femurs and tibias of B6 mice (C57BL/6 J) with 2% heat-inactivated fetal bovine serum (Equitech-Bio, Kerrville, TX, USA) in PBS, and MSCs positive for CD73, CD90, CD105, CD146, CD166, Sca-1 and SSEA-4, but negative for CD11b, CD31, CD34 and CD45, were obtained as previously described [25]. The cells with MSC character were cultured with alpha minimum essential medium (Invitrogen) supplemented with 20% fetal bovine serum and 2 mM l-glutamine (Invitrogen) in a humidified atmosphere of 95% air and 5% CO2 at 37°C for 3 days before co-culture [26]. Additionally, MSCs, which had no Fas-L, were isolated from generalized lymphoproliferative disease (gld) mice for use in comparative experiments. "
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