Department of Orthopedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanxi Medical University, 56 South Xinjian Road, Taiyuan, 030001, Shanxi, China.
J Bone Miner Metab. 2019 Jul;37(4):711-721. doi: 10.1007/s00774-018-0973-5. Epub 2018 Nov 21.
The dysregulated expression of the osteoarthritis (OA)-related genes in cartilage, such as matrix metalloproteinase 13 (MMP-13) and type X collagen (Col X), facilitates the onset and progression of OA. Reduced parathyroid hormone-related protein (PTHrP) may also accelerate this progression. Furthermore, miRNAs, endogenous regulators of mRNAs, are thought to play key roles in the pathogenesis of OA. In this study, we found that miR-195 levels were significantly upregulated in OA tissue, while PTHrP mRNA/protein expression was substantially downregulated, and there was a negative correlation between miR-195 and PTHrP. Upregulated miR-195 strongly inhibited Aggrecan, type II collagen (Col II) mRNA/protein expression, while it enhanced the expression of MMP-13 and Col X at mRNA/protein level; conversely, downregulated miR-195 significantly increased Col II mRNA/protein expression, while it decreased the expression of MMP-13 and Col X mRNA/protein. Moreover, our study demonstrated that PTHrP is a novel target of miR-195 using dual luciferase reporter assay. Finally, miR-195-mediated changes of Col II and OA-related genes were substantially attenuated by siRNA treatment. These results suggested that miR-195 is involved in the pathogenesis of OA via PTHrP.
软骨中与骨关节炎(OA)相关基因的失调表达,如基质金属蛋白酶 13(MMP-13)和 X 型胶原(Col X),促进了 OA 的发生和发展。甲状旁腺激素相关蛋白(PTHrP)的减少也可能加速这一进程。此外,miRNA,即 mRNA 的内源性调节剂,被认为在 OA 的发病机制中发挥关键作用。在本研究中,我们发现 miR-195 在 OA 组织中的水平显著上调,而 PTHrP mRNA/蛋白表达则显著下调,miR-195 与 PTHrP 之间存在负相关。上调的 miR-195 强烈抑制聚集蛋白聚糖、II 型胶原(Col II)mRNA/蛋白的表达,同时增强 MMP-13 和 Col X 在 mRNA/蛋白水平的表达;相反,下调的 miR-195 显著增加 Col II mRNA/蛋白的表达,同时降低 MMP-13 和 Col X mRNA/蛋白的表达。此外,我们的研究还通过双荧光素酶报告基因检测证实 PTHrP 是 miR-195 的一个新靶点。最后,miR-195 介导的 Col II 和 OA 相关基因的变化,通过 siRNA 处理得到了显著抑制。这些结果表明,miR-195 通过 PTHrP 参与 OA 的发病机制。