CC-chemokine ligand 20/macrophage inflammatory protein-3α and CC-chemokine receptor 6 are overexpressed in myeloma microenvironment related to osteolytic bone lesions
CC-chemokine ligand 20/macrophage inflammatory protein-3α and CC-chemokine receptor 6 are overexpressed in myeloma microenvironment related to osteolytic bone lesions
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DOI：
10.1158/0008-5472.can-08-0402
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发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Rizzoli, Vittorio
中科院分区：
文献类型：
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作者：
Giuliani, Nicola;Lisignoli, Gina;Rizzoli, Vittorio
本研究旨在探讨多发性骨髓瘤（MM）患者骨髓细胞和微环境中趋化因子CC-趋化因子配体20（CCL 20）/巨噬细胞炎性蛋白（MIP）-3 α及其受体CC-趋化因子受体6（CCR 6）的表达及其与破骨细胞（OC）形成和溶骨性骨病变的潜在关系。首先，我们发现MM细胞很少产生CCL 20/MIP-3 α，但在与可溶性因子如白细胞介素-1 β和肿瘤坏死因子α的参与下，骨髓（BM）骨祖细胞和成骨细胞共培养时，其产生上调。MM细胞还刺激共培养中OC的CCL 20/MIP-3 α和CCR 6表达。此后，我们发现CCL 20/MIP-3 α显著增加了多核抗酒石酸酸性磷酸酶阳性OC的数量和核因子κ B阳性OC祖细胞的受体激活剂，与CCL 3/MIP-1 α相似。最后，我们发现阻断抗CCL 20/MIP-3 α。抗CCR 6抗体显著抑制MM诱导的OC形成。体外数据在体内进一步扩展，共分析了64例MM患者。在MM患者中检测到的CCL 20/MIP-3 α水平显著高于意义不明的单克隆丙种球蛋白病（MGUS）受试者，在MM溶骨性患者中检测到的CCL 20/MIP-3 α水平显著高于非溶骨性患者。此外，与非溶骨性MM患者相比，溶骨性MM患者中CCL 20/MIP-3 α阳性成骨细胞显著增加。有趣的是，在MGUS和非溶骨性MM患者之间没有观察到BM CCL 20/MIP-3 α表达和水平的显著差异。我们的数据表明，CCL 20/MIP-3 α及其受体CCR 6在MM细胞的骨微环境中上调，并有助于MM患者的OC形成和溶骨性骨病变。
The expression of the chemokine CC-chemokine ligand 20 (CCL20)/macrophage inflammatory protein (MIP)-3 alpha and its receptor CC-chemokine receptor 6 (CCR6) by multiple myeloma (MM) and microenvironment cells and their potential relationship with osteoclast (OC) formation and osteolytic bone lesions in MM patients was investigated in this study. First, we found that MM cells rarely produce CCL20/MIP-3 alpha but up-regulate its production by bone marrow (BM) osteoprogenitor cells and osteoblasts in coculture with the involvement of soluble factors as interleukin-1 beta and tumor necrosis factor alpha. MM cells also stimulate both CCL20/MIP-3 alpha and CCR6 expression by OCs in coculture. Thereafter, we showed that CCL20/MIP-3 alpha significantly increases both the number of multinucleated tartrate-resistant acid phosphatase-positive OCs and receptor activator of nuclear factor-kappa B-positive OC progenitor cells similar to CCL3/MIP-1 alpha. Finally, we found that blocking anti-CCL20/MIP-3 alpha. and anti-CCR6 antibodies significantly inhibits MM-induced OC formation. In vitro data were further expanded in vivo analyzing a total number of 64 MM patients. Significantly higher CCL20/MIP-3 alpha levels were detected in MM patients versus monoclonal gammopathy of uncertain significance (MGUS) subjects and in MM osteolytic patients versus nonosteolytic ones. Moreover, a significant increase of CCL20/MIP-3 alpha-positive osteoblasts in osteolytic MM patients compared with nonosteolytic ones was observed. Interestingly, no significant difference in BM CCL20/MIP-3 alpha expression and level was observed between MGUS and nonosteolytic MM patients. Our data indicate that CCL20/MIP-3 alpha and its receptor CCR6 are up-regulated in the bone microenvironment by MM cells and contribute to OC formation and osteolytic bone lesions in MM patients.