Roles for MIP-1α and β in the development of osteolytic lesions in multiple myeloma

MIP-1α 和 β 在多发性骨髓瘤溶骨性病变发展中的作用

• 批准号: 13671067
• 负责人: ABE Masahiro
• 金额: $ 0.9万
• 依托单位: The University OF Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671067/
• 关键词: multiple myeloma; chemokine; MIP-1; osteoclast; RANKL; VLA-4

Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells -in the bone marrow and formation of devastating lytic bone lesions. Osteoclasts (OCs) fromation and bone resorption are enhanced in vitro by co-cultures with MM cells as well as addition of MM cell-conditioned media, suggesting involvement of MM-derived secreted factors and direct interaction with these cells. We have found that C-C chemokines, macrophage inflammatory protein. (MIP)-1α and β, are secreted from most of MM cells, and potently induce -OC formation _and activation. These effects are mostly abrogated by neutralizing antibodies against MIP-1α and β in combination, suggesting critical roles for these chemokines in the development of lytic bone lesions. Furthermore, secretion levels of MIP-1α and β from MM cells correlate well with the severity of bone resorption, providing a clinical evidence for a causal role of MIP=1a and b. These chemokines induce expression of RANK ligand, a key molecule of osteoclastogenesis, by, marrow stromal cells. Importantly, OC formation and activation by MM cells as well as MIP-1α and β are completely blocked by a surplus of osteoprotegerin, a soluble inhibitor of RANK ligand. These results demonstrate that the osteblytic effects of MM cells are mediated by MIP-1 in RANK-ligand-dependent manner. Moreover, MIP-1 acts on MM cells in an autocrine fashion to stimulate adhesion of MM cells to VCAM-1 by activating VLA-4, a VCAM-1 receptor abundantly expressed on MM cells. Adhesion of MM cells via VLA-4/VCAM-1 enhances the secretion of MIP-1 α, and β from MM cells, which further stimulates osteoclastogenesis. In conclusions, MIP-1α and β are among leading candidates for MM-derived factors that enhance OC differentiation and function, thereby causing extensive bone destruction. Inhibition of production and/or activities of these chemokines as well as RANK ligand may be a rational target of treatment against bone disease in MM

多发性骨髓瘤(MM)的特征是在骨髓中积聚单克隆性浆细胞，并形成破坏性的溶骨性病变。破骨细胞(OCs)的形成和骨吸收在体外通过与MM细胞共培养以及添加MM细胞条件培养液来促进，这表明MM来源的分泌因子参与并与这些细胞直接相互作用。我们已经发现C-C趋化因子、巨噬细胞炎性蛋白。(MIP)-1α和β由大多数MM细胞分泌，能有效地诱导-OC的形成和激活。这些作用大部分被抗MIP-1α和β的中和抗体联合使用而消除，这表明这些趋化因子在溶骨性病变的发展中起着关键作用。此外，MM细胞分泌MIP-1α和β的水平与骨吸收的严重程度密切相关，为MIP=1a和1b的致病作用提供了临床证据。这些趋化因子通过骨髓基质细胞诱导破骨细胞形成的关键分子RANK配体的表达。重要的是，MM细胞OC的形成和激活以及MIP-1α和β被多余的护骨素完全阻断，护骨素是RANK配体的一种可溶性抑制物。这些结果表明，MM细胞的溶骨作用是由MIP-1以等级-配体依赖的方式介导的。此外，MIP-1以自分泌的方式作用于MM细胞，通过激活MM细胞上大量表达的VCAM-1受体VLA-4来刺激MM细胞与VCAM-1的黏附。MM细胞通过vla-4/vcam-1的黏附促进MM细胞分泌α和β，从而进一步刺激破骨细胞的形成。总之，MIP-1α和β是多发性骨髓瘤衍生因子的主要候选者之一，这些因子可以增强OC的分化和功能，从而导致广泛的骨破坏。抑制这些趋化因子的产生和/或活性以及RANK配体可能是治疗MM骨病的合理靶点

项目成果

安部正博: "Critical roles of macrophage inflammatory protein (MIP)-1α and β in the development of osteolytic lesions in multiple myeloma"Blood. 100.6. 2195-2202 (2002)

Masahiro Abe：“巨噬细胞炎症蛋白（MIP）-1α和β在多发性骨髓瘤溶骨性病变发展中的关键作用”Blood 100.6（2002）。

安倍正博 他: "Critical roles of macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions of multiple myeloma"Blood. 100・6. 2195-2202 (2002)

Masahiro Abe 等：“巨噬细胞炎症蛋白 (MIP)-1α 和 MIP-1β 在多发性骨髓瘤溶骨性病变发展中的关键作用”Blood.100·6 (2002)。

Abe, M., Hiura, K., Wilde, J., Moriyama, K., Hashimoto, T., Ozaki, S., Wakatsuki, S., Kosaka, M., Kido, S., Inoue, D., Matsumoto, T.: "Critical roles of macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multip

Abe, M.、Hiura, K.、Wilde, J.、Moriyama, K.、Hashimoto, T.、Ozaki, S.、Wakatsuki, S.、Kosaka, M.、Kido, S.、Inoue, D.、 Matsumoto, T.：“巨噬细胞炎症蛋白 (MIP)-1α 和 MIP-1β 在多发性骨质疏松症溶骨性病变发展中的关键作用