Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma.
Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1alpha and MIP-1beta correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1alpha and MIP-1beta. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1alpha and MIP-1beta, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1alpha and MIP-1beta induce expression of receptor activator of nuclear factor-kappaB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1alpha and MIP-1beta may be major osteoclast-activating factors produced by MM cells.
First Department of Internal Medicine, School of Medicine, Department of Orthodontics, School of Dentistry, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Masahiro
M
Abe
Kenji
K
Hiura
Javier
J
Wilde
Keiji
K
Moriyama
Toshihiro
T
Hashimoto
Shuji
S
Ozaki
Shingo
S
Wakatsuki
Masaaki
M
Kosaka
Shinsuke
S
Kido
Daisuke
D
Inoue
Toshio
T
Matsumoto
D000818:Animals; D001859:Bone Neoplasms / Q000209:etiology; D001862:Bone Resorption / Q000209:etiology; D002352:Carrier Proteins / Q000502:physiology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D009101:Multiple Myeloma / Q000150:complications* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects; D010014:Osteolysis / Q000209:etiology*; D019899:Paracrine Communication; D053245:RANK Ligand; D011817:Rabbits; D053246:Receptor Activator of Nuclear Factor-kappa B; D019713:Receptors, CCR5 / Q000032:analysis; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D002352:Carrier Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D017077:Culture Media, Conditioned; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019713:Receptors, CCR5; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human