Department of Anatomy, University of Zagreb, School of Medicine, Zagreb, Croatia.
Lab Invest. 2010 Mar;90(3):402-13. doi: 10.1038/labinvest.2009.144. Epub 2010 Jan 18.
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.
骨量由骨细胞的分化、活性和死亡决定，主要通过细胞凋亡发生。凋亡可由成骨细胞和破骨细胞表面表达的死亡受体 Fas（CD95）触发，其可能受雌激素调控。我们之前的研究表明 Fas 信号可抑制成骨细胞分化。在本研究中，我们分析了 Fas 作为雌激素缺乏诱导骨丢失的可能介质。卵巢切除（OVX） 4 周后，与假手术动物相比，Fas 基因在破骨细胞中的表达降低，而在成骨细胞中的表达增加。Fas 基因敲除（Fas -/- ）小鼠的 OVX 不能诱导骨丢失。OVX 后 wt 小鼠破骨细胞数量增加，而 Fas -/- 小鼠则保持不变。OVX 后 Fas -/- 小鼠的成骨细胞生成受到更大的刺激，成骨细胞特异性基因表达更高。体内骨细胞分化和凋亡的直接作用在体外得到了证实，其中雌二醇的添加降低了 Fas 的表达，并部分消除了 Fas 对成骨细胞系细胞凋亡和分化的抑制作用，而对破骨细胞系细胞中 Fas 诱导的凋亡没有影响。总之，Fas 受体通过介导凋亡和抑制成骨细胞系细胞的分化，在绝经后骨质疏松症的发病机制中发挥重要作用。调节 Fas 对骨细胞的作用可能作为治疗骨吸收性疾病的治疗靶点。
