CADPE抑制RANKL诱导的破骨细胞形成和卵巢切除后的骨质丢失及其分子机理

发布时间：2018-03-04 03:11

本文选题：咖啡酸3　切入点：4-二羟基苯乙酯　出处：《华东师范大学》2011年硕士论文　论文类型：学位论文

【摘要】：RANKL刺激可以导致MAPKs/AP-1信号通路的激活和Ca2+-NFATc1的信号的启动。在破骨细胞形成中靶向这些信号通路已经成为治疗骨相关疾病的重要策略,例如绝经后的骨质疏松。在本研究中,我们检测了咖啡酸3,4-二羟基苯乙酯(CADPE)对于破骨细胞形成的影响。在小鼠的骨髓巨噬细胞和RAW264.7细胞系中,CADPE在早期抑制RANKL诱导的破骨细胞分化但是对M-CSF诱导的骨髓巨噬细胞细胞增殖和分化没有抑制作用。在分子水平上,CADPE抑制RANKL诱导的丝裂原活化蛋白激酶信号通路中ERK1/2, p38和JNK的蛋白磷酸化而对于NF-κB信号通路中IκBα的降解和p65的磷酸化没有影响。另外,CADPE抑制RANKL诱导的AP-1/c-Fos的入核和活性,并且过表达c-Fos阻止了CADPE对于破骨细胞形成的抑制作用。CADPE还能够抑制RANKL诱导的钙离子的振荡,降低破骨细胞形成相关基因的表达,包括NFATcl, TRAP, cathepsin K和c-Src。为了检测CADPE对于破骨细胞活性在体内的效果,我们还检测了在卵巢切除诱导的骨质疏松模型中CADPE的效果,实验结果表明CADPE可以抑制卵巢切除导致的骨缺失。总之,我们的数据表明CADPE可通过抑制MAPKs和Ca2+-NFATc1信号通路来抑制RANKL诱导的破骨细胞形成和骨缺失。因此,CADPE成为治疗骨质疏松等破骨细胞相关疾病的新的候选药物。
[Abstract]:RANKL stimulation can lead to activation of MAPKs/AP-1 signaling pathways and activation of Ca2 -NFATc1 signaling pathways. Targeting these signaling pathways in osteoclast formation has become an important strategy in the treatment of bone-related diseases, such as postmenopausal osteoporosis. We examined the effects of caffeic acid 3- (4-dihydroxyphenyl ethyl ester) on osteoclast formation. In murine bone marrow macrophages and RAW264.7 cell lines, CADPE inhibited the differentiation of osteoclasts induced by RANKL at an early stage but induced bone marrow macrosomia by M-CSF. At the molecular level, CADPE inhibited the phosphorylation of ERK1 / 2, p38 and JNK proteins in the mitogen-activated protein kinase signaling pathway induced by RANKL, but inhibited the degradation of I 魏 B 伪 and p65 in NF- 魏 B signaling pathway. In addition, CADPE inhibited the nucleation and activity of AP-1/c-Fos induced by RANKL. Furthermore, overexpression of c-Fos blocked the inhibition of osteoclast formation by CADPE. CADPE also inhibited the calcium oscillation induced by RANKL, and decreased the expression of osteoclast formation-related genes. In order to test the effect of CADPE on osteoclast activity in vivo, we also examined the effect of CADPE in ovariectomized osteoporosis models. The results show that CADPE can inhibit bone loss caused by ovariectomy. Our data suggest that CADPE can inhibit osteoclast formation and bone loss induced by RANKL by inhibiting MAPKs and Ca2 -NFATc1 signaling pathway. Therefore, CADPE is a new candidate for the treatment of osteoclast-related diseases such as osteoporosis.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R329.2

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