Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China.
Department of Endocrinology, Punan Hospital of Pudong New District, Shanghai 200125, P.R. China.
Mol Med Rep. 2018 Jan;17(1):1609-1616. doi: 10.3892/mmr.2017.8042. Epub 2017 Nov 14.
The present study aimed to investigate whether 17β‑estradiol (E2) exerts protective effects on bone deterioration induced by ovariectomy (OVX) through the ephA2/ephrinA2 signaling pathway in rats. Female rats were subjected to OVX, sham surgeryor OVX+E2 treatment. Levels of biomarkers were measured in serum and urine. Hematoxylin and eosin staining was performed on paraffin‑embedded bone sections. Expression of genes and proteins was analyzed by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. Bone mineral density (BMD) was analyzed by dual‑energy X‑ray absorptiometry. Trabecular bone microarchitecture was also evaluated. Osteoclastogenesis was induced by in vitro culturing with mouse receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony‑stimulating factor 1. small interfering RNA was designed to knockdown ehpA2 receptor and its ligand ephrinA2. Results of the present study demonstrated that E2 had suppressive effects on OVX‑induced body weight gain and bone turnover factors in serum and urine. E2 inhibited the bone resorption function of osteoclasts by inhibiting the production of tartrate‑resistant acid phosphatase‑5b and RANKL, and induced bone formation function of osteoblasts by prompting runt‑related transcription factor 2, Sp7 transcription factor and collagen alpha‑1(I) chain expression in bone marrow cells. E2 treatment significantly increased the tibia BMD and prevented the deterioration of trabecular microarchitecture compared with the OVX group. Moreover, E2 significantly decreased the OVX‑stimulated expression of ephA2 and ephrinA2. EphA2 or ephrin A2 knockdown significantly suppressed osteoclastogenesis in vitro. In conclusion, E2 can attenuate OVX‑induced bone deterioration partially through the suppression of the ephA2/ephrinA2 signaling pathway. Therefore EphA2/ephrinA2 signaling pathway may be a potential target for osteoporosis treatment.
本研究旨在探讨 17β-雌二醇（E2）是否通过 EphA2/ephrinA2 信号通路对去卵巢（OVX）诱导的大鼠骨恶化发挥保护作用。雌性大鼠接受 OVX、假手术或 OVX+E2 治疗。测量血清和尿液中的生物标志物水平。对石蜡包埋的骨切片进行苏木精和伊红染色。通过逆转录-定量聚合酶链反应和蛋白质印迹分别分析基因和蛋白质的表达。通过双能 X 射线吸收法分析骨矿物质密度（BMD）。还评估了小梁骨微结构。通过体外培养鼠核因子 κB 受体激活剂配体（RANKL）和巨噬细胞集落刺激因子 1 诱导破骨细胞生成。设计小干扰 RNA 以敲低 ehpA2 受体及其配体 ephrinA2。本研究结果表明，E2 对 OVX 诱导的体重增加和血清和尿液中的骨转换因子具有抑制作用。E2 通过抑制抗酒石酸酸性磷酸酶-5b 和 RANKL 的产生抑制破骨细胞的骨吸收功能，并通过刺激骨髓细胞中 runt 相关转录因子 2、Sp7 转录因子和胶原α-1（I）链的表达诱导成骨细胞的骨形成功能。E2 治疗可显著增加胫骨 BMD，并防止与 OVX 组相比，小梁微结构恶化。此外，E2 显著降低了 OVX 刺激的 ehpA2 和 ephrinA2 的表达。EphA2 或 ephrin A2 敲低可显著抑制体外破骨细胞生成。综上所述，E2 可通过抑制 EphA2/ephrinA2 信号通路部分减轻 OVX 诱导的骨恶化。因此，EphA2/ephrinA2 信号通路可能是骨质疏松症治疗的潜在靶点。
