Interaction of Fas ligand and Fas expressed on osteoclast precursors increases osteoclastogenesis
Interaction of Fas ligand and Fas expressed on osteoclast precursors increases osteoclastogenesis
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DOI：
10.4049/jimmunol.175.11.7193
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Choi, YN
中科院分区：
文献类型：
--
作者：
Park, H;Jung, YK;Choi, YN
我们偶然发现，破骨细胞前体细胞和成熟破骨细胞表达Fas配体（FasL）以及Fas，这是证实了流式细胞术，免疫荧光染色，和RT-PCR。本研究的目的是确定FasL在破骨细胞分化和细胞死亡中的作用。为了研究FasL在破骨细胞生成中的作用，在使用骨髓源性巨噬细胞的NF-κ B配体受体激活剂（RANKL）诱导的破骨细胞生成期间加入中和性抗FasL mAb或rFasL。抗FasL单克隆抗体中和内源性FasL可降低破骨细胞的生成，而rFasL则以剂量依赖性方式增强破骨细胞的分化。此外，rFasL上调破骨细胞因子如IL-1 β和TNF-α的分泌，以及NF-κ B B的活化。使用IL-1受体拮抗剂和可溶性TNFR功能性阻断IL-β和TNF-α证实了这些细胞因子介导FasL对破骨细胞生成的作用。破骨细胞前体对rFasL诱导的细胞凋亡具有相对抗性，尤其是在RANKL处理前，导致破骨细胞生成期间rFasL处理的细胞损失最小。虽然rFasL增加了成熟破骨细胞的细胞死亡，生长因子的撤出诱导更多的细胞死亡。但抗FasL单抗对成熟破骨细胞的存活无影响，提示内源性FasL在破骨细胞凋亡中不起作用。最后，与对细胞凋亡的影响相反，rFasL辅助的破骨细胞生成不是由半胱天冬酶介导的。总之，FasL通过促进破骨细胞的分化在骨稳态中具有新的功能，这是以前没有考虑到的。
We incidentally found that osteoclast precursors and mature osteoclasts express Fas ligand (FasL) as well as Fas, which was confirmed by flow cytometry, immunofluorescent staining, and RT-PCR. The aim of this study was to determine the role of FasL in differentiation and cell death of osteoclasts. To study the role of FasL in osteoclastogenesis, neutralizing anti-FasL mAb or rFasL was added during receptor activator of NF-kappa B ligand (RANKL)-induced osteoclastogenesis using bone marrow-derived macrophages. Neutralization of endogenous FasL by anti-FasL mAb decreased osteoclastogenesis, whereas rFasL enhanced osteoclast differentiation in a dose-dependent manner. In addition, rFasL up-regulated the secretion of osteoclastogentic cytokines, such as IL-1 beta and TNF-alpha, and the activation of NF-kappa B. Functional blocking of IL-beta and TNF-a using IL-1 receptor antagonist and soluble TNFR confirmed that those cytokines mediated the effect of FasL on osteoclastogenesis. The osteoclast precursors were relatively resistant to rFasL-induced apoptosis especially before RANKL treatment, resulting in minimal cell loss by rFasL treatment during osteoclastogenesis. Although rFasL increased the cell death of mature osteoclasts, growth factor withdrawal induced much more cell death. However, anti-FasL mAb did not affect the survival of mature osteoclasts, suggesting that the endogenous FasL does not have a role in the apoptosis of osteoclasts. Finally, in contrast to the effect on apoptosis, rFasL-assisted osteoclastogenesis was not mediated by caspases. In conclusion, FasL has a novel function in bone homeostasis by enhancing the differentiation of osteoclasts, which was not considered previously.