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

Recent data have implicated macrophage inflammatory protein-1α (MIP-1α) 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-1α requires other factors such as receptor activator of nuclear factor-λB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1α 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-1α on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1α (CHO/MIP-1α) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1α 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-1α tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1α tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP⁺) osteoclasts. Injection of recombinant MIP-1α over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1α had no effect in RANK^-/- mice. Together, these results establish that MIP-1α 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-1α exerts a dual effect in myeloma, on osteoclasts, and tumor cells.