Cyclosporine A and FK506 induce osteoclast apoptosis in mouse bone marrow cell cultures
Cyclosporine A and FK506 induce osteoclast apoptosis in mouse bone marrow cell cultures
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DOI：
10.1016/j.bone.2004.02.009
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发表时间：
2004-07-01
期刊：
影响因子：
4.1
通讯作者：
Stern, PH
中科院分区：
文献类型：
--
作者：
Igarashi, K;Hirotani, H;Stern, PH
进行研究以表征环孢菌素和 FK506 对小鼠骨髓培养物来源的破骨细胞形成和存活的影响。环孢菌素 A (CsA)、环孢菌素 B (CsB)、环孢菌素 H (CsH) 和 FK506 均抑制 NFkappaB 配体受体激活剂 (RANKL) 刺激的抗酒石酸酸性磷酸酶 (TRAP) 活性以及培养物中 TRAP+ 多核细胞的生成。 CsA和CsG大致等价，CsH比其他环孢菌素效力大约低一个数量级，而FK506比CsA和CsG效力大约两个数量级。所有抑制剂在减少 TRAP+ 多核细胞数量方面均表现出比减少总 TRAP 活性更大的效力和功效。在实验中获得了进一步的证据，表明晚期阶段对抑制更敏感，在这些实验中，CsA 在 RANKL 刺激的培养期的不同阶段都存在。在 4 天培养的最后 2 天添加 CsA 与在整个培养期间添加 CsA 一样有效，而如果仅在培养的前 2 天添加，则效果较差。当向已形成破骨细胞的培养物中添加 CsA 或 FK506 1 天时，TRAP+ 破骨细胞的数量减少。 CsA 或 FK506 处理会导致多核破骨细胞的核碎裂和破坏，并且 caspase-3 活性增加。凋亡抑制剂 z-VAD 部分阻止了 CsA 和 FK506 对培养物中 TRAP+ 多核细胞存活的抑制作用，并且还保留了正常的破骨细胞形态。数据表明CsA和FK506对骨髓源性破骨细胞的抑制作用的一个重要组成部分是诱导细胞凋亡。 (C) 2004 Elsevier Inc. 保留所有权利。
Studies were carried out to characterize the effects of cyclosporines and FK506 on the formation and survival of osteoclasts deriving from mouse bone marrow cultures. Cyclosporin A (CsA), cyclosporin B (CsB), cyclosporin H (CsH), and FK506 all inhibited receptor activator of NFkappaB ligand (RANKL)-stimulated tartratc-resistant acid phosphatase (TRAP) activity and generation of TRAP+ multinucleated cells in the cultures. CsA and CsG were approximately equipotent, CsH was approximately one order of magnitude less potent than the other cyclosporines, and FK506 was approximately two orders of magnitude more potent than CsA and CsG. All of the inhibitors demonstrated greater potency and efficacy on decreasing the number of TRAP+ multinucleated cells than on decreasing total TRAP activity. Further evidence that late stages were more sensitive to inhibition was obtained in experiments in which CsA was present for different segments of the RANKL-stimulated culture period. CsA was as efficacious when added for the final 2 days of a 4-day culture as when added for the entire culture period, whereas it was less effective if added for only the first 2 days of the culture. When CsA or FK506 were added for I day to cultures in which osteoclasts had already formed, the numbers of TRAP+ osteoclasts decreased. Treatment with CsA or FK506 produced nuclear fragmentation and disruption of the multinucleated osteoclasts and an increase in caspase-3 activity. The apoptosis inhibitor z-VAD partially prevented the inhibitory effects of CsA and FK506 on the survival of TRAP+ multinucleated cells in the cultures and also preserved the normal osteoclast morphology. The data indicate that an important component of the inhibitory effects of CsA and FK506 on marrow-derived osteoclasts is the induction of apoptosis. (C) 2004 Elsevier Inc. All rights reserved.