Effects of immunosuppressants on receptor activator of NF-κB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells
Effects of immunosuppressants on receptor activator of NF-κB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells
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DOI：
10.1006/bbrc.2000.4130
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发表时间：
2001-01-12
影响因子：
3.1
通讯作者：
Khosla, S
中科院分区：
文献类型：
--
作者：
Hofbauer, LC;Shui, CX;Khosla, S
骨质疏松症和血管病变是器官移植后常见的疾病，主要归因于免疫抑制剂的使用。骨保护素（OPG）由成骨细胞和动脉细胞产生，通过中和NF-κ B配体受体激活剂（RANKL）抑制破骨细胞功能。由于OPG缺陷小鼠发生骨质疏松症和动脉钙化，我们评估了免疫抑制剂对人成骨细胞和冠状动脉平滑肌细胞（CASMC）OPG和RANKL表达的影响。环孢霉素A、雷帕霉素和FK-506可降低未分化骨髓基质细胞中OPG mRNA和蛋白水平（分别降低63、44和68%，P < 0.001）。所有三种免疫抑制剂均使这些细胞中的RANKL mRNA水平增加60%至210%。与对骨髓基质细胞的这些作用相反，雷帕霉素可能相对地保留骨，在成熟成骨细胞中增加OPG mRNA和蛋白质的产生（120%，P < 0.001）。环孢霉素A也使CASMC OPG mRNA和蛋白的表达减少52%（P < 0.001）。总之，免疫抑制剂减少OPC：mRNA和蛋白质的生产和增加RANKL基因表达的骨髓基质细胞，环孢素抑制OPG生产CASMC。因此，这些研究提供了免疫抑制剂诱导的骨丢失的潜在机制，以及环孢素A 60导致血管疾病的倾向。(C)北京：科学出版社.
Osteoporosis and vasculopathy are common after organ transplantation and have been largely attributed to the use of immunosuppressants. Osteoprotegerin (OPG) is produced by osteoblastic and arterial cells, and inhibits osteoclast functions by neutralizing receptor activator of NF-kappaB ligand (RANKL). Because OPG-deficient mice develop osteoporosis and arterial calcification, we assessed the effects of immunosuppressants on OPG and RANKL expression by human osteoblastic and coronary artery smooth muscle cells (CASMC). Cyclosporine A, rapamycin, and FK-506 decreased OPG mRNA and protein levels in undifferentiated marrow stromal cells (by 63, 44, and 68%, respectively, P < 0.001). All three immunosuppressants increased RANKL mRNA levels in these cells by 60 to 210%. In contrast to these effects on marrow stromal cells, rapamycin, which may be relatively bone-sparing, increased OPG mRNA and protein production (by 120%, P < 0.001) in mature osteoblastic cells. Cyclosporine A also decreased OPG mRNA and protein production (by 52%, P < 0.001) of CASMC. In conclusion, immunosuppressants decrease OPC: mRNA and protein production and increase RANKL gene expression by marrow stromal cells, and cyclosporine suppresses OPG production in CASMC. These studies thus provide a potential mechanism for immunosuppressant-induced bone loss, and the propensity of cyclosporine A 60 cause vascular disease. (C) 2001 Academic Press.