Fas receptor is required for estrogen deficiency-induced bone loss in mice
Fas receptor is required for estrogen deficiency-induced bone loss in mice
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DOI：
10.1038/labinvest.2009.144
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发表时间：
2010-03-01
影响因子：
5
通讯作者：
Marusic, Ana
中科院分区：
文献类型：
--
作者：
Kovacic, Natasa;Grcevic, Danka;Marusic, Ana
骨量是由骨细胞分化、活性和死亡决定的，主要通过细胞凋亡发生。细胞凋亡可由死亡受体Fas （CD95）触发，表达于成骨细胞和破骨细胞，并可能受雌激素调节。我们之前已经证明通过Fas的信号传导抑制成骨细胞分化。在这项研究中，我们分析了Fas作为雌激素戒断引起骨质流失的可能介质。卵巢切除术（OVX）后4周，与假手术动物相比，切除卵巢的C57BL/6J（野生型（wt））小鼠成骨细胞中Fas基因表达较高，破骨细胞中Fas基因表达较低。在Fas基因敲除的小鼠（Fas -/-小鼠）中，OVX不能诱导骨质流失。OVX后wt小鼠的破骨细胞数量增加，而Fas -/-小鼠的破骨细胞数量保持不变。OVX诱导Fas -/-小鼠的成骨形成比wt小鼠更大，成骨特异性基因的表达更高。体外实验证实了在体内对骨细胞分化和凋亡的直接影响，在体外实验中，雌二醇的加入降低了Fas的表达，部分消除了Fas在成骨细胞系细胞中的凋亡和分化抑制作用，而对Fas诱导的破骨细胞系细胞凋亡没有影响。综上所述，Fas受体通过介导成骨细胞凋亡和抑制成骨细胞分化，在绝经后骨质疏松的发病机制中发挥了重要作用。调节Fas对骨细胞的影响可能被用作治疗骨吸收性疾病的治疗靶点。
Bone mass is determined by bone cell differentiation, activity, and death, which mainly occur through apoptosis. Apoptosis can be triggered by death receptor Fas (CD95), expressed on osteoblasts and osteoclasts and may be regulated by estrogen. We have previously shown that signaling through Fas inhibits osteoblast differentiation. In this study we analyzed Fas as a possible mediator of bone loss induced by estrogen withdrawal. At 4 weeks after ovariectomy (OVX), Fas gene expression was greater in osteoblasts and lower in osteoclasts in ovariectomized C57BL/6J (wild type (wt)) mice compared with sham-operated animals. OVX was unable to induce bone loss in mice with a gene knockout for Fas (Fas -/- mice). The number of osteoclasts increased in wt mice after OVX, whereas it remained unchanged in Fas -/- mice. OVX induced greater stimulation of osteoblastogenesis in Fas -/- than in wt mice, with higher expression of osteoblast-specific genes. Direct effects on bone cell differentiation and apoptosis in vivo were confirmed in vitro, in which addition of estradiol decreased Fas expression and partially abrogated the apoptotic and differentiation-inhibitory effect of Fas in osteoblast lineage cells, while having no effect on Fas-induced apoptosis in osteoclast lineage cells. In conclusion, the Fas receptor has an important role in the pathogenesis of postmenopausal osteoporosis by mediating apoptosis and inhibiting differentiation of osteoblast lineage cells. Modulation of Fas effects on bone cells may be used as a therapeutic target in the treatment of osteoresorptive disorders.