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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2195-2202
NEOPLASIA
Role for macrophage inflammatory protein (MIP)-1 and MIP-1
in the development of osteolytic lesions in multiple myeloma
Masahiro Abe,
Kenji Hiura,
Javier Wilde,
Keiji Moriyama,
Toshihiro Hashimoto,
Shuji Ozaki,
Shingo Wakatsuki,
Masaaki Kosaka,
Shinsuke Kido,
Daisuke Inoue, and
Toshio Matsumoto
From the First Department of Internal Medicine, School
of Medicine, Department of Orthodontics, School of Dentistry, and First
Department of Pathology, School of Medicine, University of Tokushima,
and Tokushima Prefectural Hospital Kaifu, Tokushima, Japan.
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)-1 and
MIP-1 , 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-1 and MIP-1 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-1 and MIP-1.
Importantly, these effects were mostly reversed by neutralizing
antibodies against MIP-1 and MIP-1, or their cognate receptor,
CCR5, suggesting critical roles of these chemokines. We also
demonstrated that stromal cells express CCR5 and that recombinant
MIP-1 and MIP-1 induce expression of receptor activator of
nuclear factor- B (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1 and MIP-1 may be major osteoclast-activating factors produced by MM cells.
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