Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment
Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment
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DOI：
10.1182/blood.v98.13.3527
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发表时间：
2001-12-15
期刊：
影响因子：
20.3
通讯作者：
Barillé, S
中科院分区：
文献类型：
--
作者：
Giuliani, N;Bataille, R;Barillé, S
尽管骨质溶解是多发性骨髓瘤（MM）患者的常见并发症，但MM诱导的骨病发病机制所涉及的生物学机制仍知之甚少。由基质成骨细胞产生的两种因子似乎对骨吸收的调节至关重要：骨保护素（OPG）及其配体（OPGL）。OPGL刺激破骨细胞的分化和活性，而OPG抑制这些过程。本研究调查了骨髓瘤细胞是否影响骨髓（BM）环境中的生理OPG/ OPGL平衡。10个人骨髓瘤细胞系和从26个连续MM患者中分离的骨髓瘤细胞不能表达OPGL，并且仅很少产生少量的OPG。在共培养系统中，人骨髓瘤细胞上调OPGL表达，但在mRNA和蛋白水平上强烈下调原代人BM的前成骨细胞（preOB）或基质细胞（BMSC）中OPG的产生。这种作用依赖于骨髓瘤细胞与BMSC或preOB之间的细胞与细胞接触，部分涉及整合素VLA-4。此外，与健康供体相比，从MM患者获得的离体BM培养物中发生OPGL mRNA的过表达，对BM活检标本进行的免疫组织化学染色显示，与健康受试者相比，MM患者中OPGL表达增加，OPG表达减少。总之，这些数据表明骨髓瘤细胞影响BM环境中的OPG/OPGL比率，并倾向于证实OPG/OPGL系统参与MM诱导的骨病的发病机制。(C)2001年，美国血液学会。
Although osteolysis is a common complication in patients with multiple myeloma (MM), the biologic mechanisms involved in the pathogenesis of MM-induced bone disease are poorly understood. Two factors produced by stromal-osteoblastic cells seem critical to the regulation of bone resorption: osteoprotegerin (OPG) and its ligand (OPGL). OPGL stimulates osteoclast differentiation and activity, whereas OPG inhibits these processes. The present study investigated whether myeloma cells affect physiologic OPG/ OPGL balance in the bone marrow (BM) environment. Ten human myeloma cell lines and myeloma cells isolated from 26 consecutive patients with MM failed to express OPGL and only rarely produced a low amount of OPG. In a coculture system, human myeloma cells up-regulated OPGL expression but strongly downregulated OPG production in preosteoblastic (preOB) or stromal cells (BMSCs) of primary human BM at the mRNA and protein levels. This effect, which was dependent on cell-to-cell contact between myeloma cells and BMSCs or preOB, partially involved the integrin VLA-4. In addition, overexpression of OPGL mRNA occurred in ex vivo BM cultures obtained from MM patients as compared with healthy donors, and immunohistochemical staining performed on BM biopsy specimens showed an increase of OPGL and a reduction of OPG expression in MM patients as compared with healthy subjects. In summary, these data indicate that myeloma cells affect the OPG/OPGL ratio in the BM environment and tend to confirm that the OPG/OPGL system is involved in the pathogenesis of MM-induced bone disease. (C) 2001 by The American Society of Hematology.