Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma
Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma
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DOI：
10.1182/blood.v100.6.2195.h81802002195_2195_2202
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发表时间：
2002-09-15
期刊：
影响因子：
20.3
通讯作者：
Matsumoto, T
中科院分区：
文献类型：
--
作者：
Abe, M;Hiura, K;Matsumoto, T
多发性骨髓瘤（MM）细胞通过激活骨髓环境中的破骨细胞引起破坏性骨破坏。然而，骨髓瘤患者骨吸收增强的机制知之甚少。在本研究中，我们研究了C-C趋化因子巨噬细胞炎性蛋白（MIP）-1 α和MIP-1 β在MM细胞诱导的骨质溶解中的作用。这些趋化因子由大多数MM细胞系以及来自患者的原代MM细胞产生和分泌。MIP-1 α和MIP-1 β的分泌与骨髓瘤细胞在体外和体内以及MM患者中增强骨细胞骨吸收的能力密切相关。在兔骨细胞的破骨细胞生成培养物中，与骨髓瘤细胞共培养以及加入骨髓瘤细胞条件培养基增强了破骨细胞样细胞和吸收陷窝的形成，其程度与重组MIP-1 α和MIP-1 β的作用相当。重要的是，这些作用大多被针对MIP-1 α和MIP-1 β或其同源受体CCR5的中和抗体逆转，表明这些趋化因子的关键作用。我们还证明了基质细胞表达CCR5，重组MIP-1 α和MIP-1 β诱导基质细胞表达核因子-κ B受体激活因子（RANK）配体，从而刺激破骨细胞分化的前骨细胞。提示MIP-1 α和MIP-1 β可能是MM细胞产生的主要破骨细胞活化因子。
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.