Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease
| Autor: | Barbara Sherry, Anjana Gupta, Paul J. Williams, Di Chen, Barry Grubbs, Donna Pulkrabek, Babatunde O. Oyajobi, Ming Zhao, Gregory R. Mundy, Giovanni Franchin, Steve Munoz |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Pathology
medicine.medical_specialty Osteolysis Bone disease Immunology Osteoclasts Injections Intralesional Biochemistry Mice In vivo Osteoclast medicine Animals Bone Resorption Chemokine CCL4 Macrophage inflammatory protein Multiple myeloma Chemokine CCL3 CD40 biology Skull Antibodies Monoclonal Cell Biology Hematology Macrophage Inflammatory Proteins medicine.disease Recombinant Proteins Disease Models Animal medicine.anatomical_structure RANKL Hypercalcemia biology.protein Multiple Myeloma |
| Zdroj: | Blood. 102:311-319 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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-κB 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. (Blood. 2003;102:311-319) |
| Databáze: | OpenAIRE |
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