Decreased microRNA-182-5p helps alendronate promote osteoblast proliferation and differentiation in osteoporosis via the Rap1/MAPK pathway
Decreased microRNA-182-5p helps alendronate promote osteoblast proliferation and differentiation in osteoporosis via the Rap1/MAPK pathway
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DOI：
10.1042/bsr20180696
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发表时间：
2018-12-21
影响因子：
4
通讯作者：
Pan, Li
中科院分区：
文献类型：
--
作者：
Pan, Bao-Long;Tong, Zong-Wu;Pan, Li
骨质疏松症（OP）是一种严重的健康问题，导致骨质结构损伤和骨脆性。microRNAs（miRNAs）在骨内分泌中发挥重要作用。因此，阐明miRNAs在骨内分泌生理和病理中的表达和功能，对提高代谢相关性骨病的潜在治疗价值具有重要意义。我们通过Rap 1/丝裂原活化蛋白激酶（MAPK）信号通路靶向腺苷酸环化酶亚型6（ADCY 6），探讨microRNA-182- 5 p（miR-182- 5 p）对阿仑膦酸钠（ALN）治疗后OP大鼠成骨细胞增殖和分化的影响。建立OP大鼠模型，观察ALN对OP的影响，并检测miR-182- 5 p、ADCY 6及Rap 1/MAPK信号通路相关基因的表达。为了确定miR-182- 5 p和ADCY 6在ALN治疗后OP中的作用，初步验证了miR-182和ADCY 6之间的关系。随后提取成骨细胞并用miR-182- 5 p抑制剂、miR-182- 5 p模拟物、si-ADCY 6和MAPK信号传导途径抑制剂U 0126转染。同时测定细胞增殖、凋亡和分化情况。ALN治疗能够缓解OP的症状。miR-182- 5 p负靶向ADCY 6以抑制Rap 1/MAPK信号通路。转染miR-182抑制剂的细胞ALP、BGP和COL I表达降低，表明miR-182- 5 p的下调促进细胞分化和增殖，抑制细胞凋亡。结论：下调miR-182- 5 p可通过上调ADCY 6激活Rap 1/MAPK信号通路促进OP大鼠成骨细胞的增殖和分化，这可能是治疗OP的新靶点。
Osteoporosis (OP) is a serious health problem that contributes to osteoporotic structural damage and bone fragility. MicroRNAs (miRNAs) can exert important functions over bone endocrinology. Therefore, it is of substantial significance to clarify the expression and function of miRNAs in bone endocrine physiology and pathology to improve the potential therapeutic value for metabolism-related bone diseases. We explored the effect of microRNA-182-5p (miR-182-5p) on osteoblast proliferation and differentiation in OP rats after alendronate (ALN) treatment by targeting adenylyl cyclase isoform 6 (ADCY6) through the Rap1/mitogen-activated protein kinase (MAPK) signaling pathway. Rat models of OP were established to observe the effect of ALN on OP, and the expression of miR-182-5p, ADCY6 and the Rap1/MAPK signaling pathway-related genes was determined. To determine the roles of miR-182-5p and ADCY6 in OP after ALN treatment, the relationship between miR-182 and ADCY6 was initially verified. Osteoblasts were subsequently extracted and transfected with a miR-182-5p inhibitor, miR-182-5p mimic, si-ADCY6 and the MAPK signaling pathway inhibitor U0126. Cell proliferation, apoptosis and differentiation were also determined. ALN treatment was able to ease the symptoms of OP. miR-182-5p negatively targeted ADCY6 to inhibit the Rap1/MAPK signaling pathway. Cells transfected with miR-182 inhibitor decreased the expression of ALP, BGP and COL I, which indicated that the down-regulation of miR-182-5p promoted cell differentiation and cell proliferation and inhibited cell apoptosis. In conclusion, the present study shows that down-regulated miR-182-5p promotes the proliferation and differentiation of osteoblasts in OP rats through Rap1/MAPK signaling pathway activation by up-regulating ADCY6, which may represent a novel target for OP treatment.