title: Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease.
abstract: 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.
authors.affiliation: Department of Cellular and Structural Biology (MSC 7762), University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. oyajobi@uthscsa.edu
authors.forename: Babatunde O
authors.initials: BO
authors.lastname: Oyajobi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Franchin
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Williams
authors.forename: Donna
authors.initials: D
authors.lastname: Pulkrabek
authors.forename: Anjana
authors.initials: A
authors.lastname: Gupta
authors.forename: Steve
authors.initials: S
authors.lastname: Munoz
authors.forename: Barry
authors.initials: B
authors.lastname: Grubbs
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Barbara
authors.initials: B
authors.lastname: Sherry
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Mundy
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001862:Bone Resorption / Q000139:chemically induced; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004195:Disease Models, Animal; D006934:Hypercalcemia; D015552:Injections, Intralesional; D019402:Macrophage Inflammatory Proteins / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010014:Osteolysis / Q000188:drug therapy* / Q000209:etiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012886:Skull / Q000166:cytology
chemical_list: D000911:Antibodies, Monoclonal; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins