Department of Laboratory, People's Hospital of Yuxi City, Yuxi 653100, P.R. China.
Department of Nephrology, People's Hospital of Yuxi City, Yuxi 653100, P.R. China.
Biosci Rep. 2018 Dec 21;38(6). doi: 10.1042/BSR20180696.
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.
骨质疏松症（OP）是一种严重的健康问题，会导致骨质疏松的结构损伤和骨骼脆弱。微小 RNA（miRNA）可以对骨骼内分泌发挥重要作用。因此，阐明 miRNA 在骨骼内分泌生理学和病理学中的表达和功能，对于提高与代谢相关的骨骼疾病的潜在治疗价值具有重要意义。我们通过 Rap1/丝裂原活化蛋白激酶（MAPK）信号通路，探讨了 miR-182-5p（miR-182-5p）靶向腺苷酸环化酶同工酶 6（ADCY6）对阿仑膦酸钠（ALN）治疗 OP 大鼠成骨细胞增殖和分化的影响。建立大鼠 OP 模型，观察 ALN 对 OP 的影响，测定 miR-182-5p、ADCY6 及 Rap1/MAPK 信号通路相关基因的表达。为了确定 miR-182-5p 和 ADCY6 在 ALN 治疗 OP 后的作用，初步验证了 miR-182 与 ADCY6 的关系。提取成骨细胞并转染 miR-182-5p 抑制剂、miR-182-5p 模拟物、si-ADCY6 和 MAPK 信号通路抑制剂 U0126，测定细胞增殖、凋亡和分化。ALN 治疗可缓解 OP 症状。miR-182-5p 负向靶向 ADCY6 抑制 Rap1/MAPK 信号通路。转染 miR-182 抑制剂的细胞降低了碱性磷酸酶、骨钙素和 I 型胶原的表达，表明 miR-182-5p 的下调促进了细胞分化、细胞增殖并抑制了细胞凋亡。综上所述，本研究表明，下调的 miR-182-5p 通过上调 ADCY6 激活 Rap1/MAPK 信号通路，促进 OP 大鼠成骨细胞的增殖和分化，可能成为治疗 OP 的新靶点。
