Hospital and Instistute of Obstetrics and Gynecology, IBS, Fudan University, NO. 419 Fangxie Road, Shanghai, 200011, China.
Hospital and Instistute of Obstetrics and Gynecology, IBS, Fudan University, NO. 419 Fangxie Road, Shanghai, 200011, China.
Biochem Biophys Res Commun. 2019 Sep 10;517(1):103-110. doi: 10.1016/j.bbrc.2019.07.025. Epub 2019 Jul 18.
Recently, the emerging role of microRNAs (miRNAs) has been identified in osteogenesis and the development of osteoporosis. Here, we found that miR-545-3p was decreased with the progression of osteogenic differentiation of MC3T3-E1 cells. Gain-of-function assay elucidated that ectopic expression of miR-545-3p led to abolishment on the levels of osteogenic differentiation markers including OC, ALP and Runx2, as well as increase on the expression of SOST, a negative regulator of osteogenic differentiation. Meanwhile, we explained that the inhibitory role of miR-545-3p in the proliferation of differentiated MC3T3-E1 cells was attributed to its induction on apoptosis. Furthermore, the mechanistic investigations validated that miR-545-3p inactivated Wnt/β-catenin signaling pathway by post-transcriptionally silencing LRP5. Importantly, we verified that miR-545-3p-confined osteogenic differentiation was mediated by the inhibition of LRP5-dependent Wnt/β-catenin pathway. Furthermore, it was identified that miR-545-3p downregulation in osteogenic differentiation was due to the positive transcriptional regulation by SP1, an osteoporosis-promoting transcription factor that was proved to be lessened along with osteoblastic differentiation. Jointly, this study elaborated that the SP1-modulated miR-545-3p functions as an osteogenesis-inhibitory factor through targeting LRP5 to inactivate Wnt/β-catenin signaling. Remarkably, strategies targeting miR-545-3p might be an innovative idea for the therapy of patients with osteoporosis.
最近，miRNAs（microRNAs）在成骨作用和骨质疏松症的发展中的新兴作用已经被确定。在这里，我们发现 miR-545-3p 在 MC3T3-E1 细胞的成骨分化过程中随着其进展而减少。功能获得试验阐明，miR-545-3p 的异位表达导致成骨分化标志物（包括 OC、ALP 和 Runx2）的水平降低，以及 SOST（成骨分化的负调节剂）的表达增加。同时，我们解释说，miR-545-3p 对分化的 MC3T3-E1 细胞增殖的抑制作用归因于其诱导细胞凋亡。此外，机制研究验证了 miR-545-3p 通过转录后沉默 LRP5 来失活 Wnt/β-catenin 信号通路。重要的是，我们验证了 miR-545-3p 对成骨分化的限制是通过抑制 LRP5 依赖的 Wnt/β-catenin 通路介导的。此外，确定了 miR-545-3p 在成骨分化中的下调是由于 SP1 的正转录调节，SP1 是一种促进骨质疏松的转录因子，其随着成骨细胞分化而减少。总之，这项研究阐述了 SP1 调节的 miR-545-3p 通过靶向 LRP5 来失活 Wnt/β-catenin 信号，作为一种成骨抑制因子发挥作用。值得注意的是，针对 miR-545-3p 的策略可能是骨质疏松症患者治疗的一种创新思路。
