Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Bone Miner Res. 2014 Feb;29(2):316-26. doi: 10.1002/jbmr.2040.
MicroRNAs (miRNAs) are endogenous small noncoding RNAs regulating the activities of target mRNAs and cellular processes. Although no miRNA has been reported to play an important role in the regulation of fracture healing, several miRNAs control key elements in tissue repair processes such as inflammation, hypoxia response, angiogenesis, stem cell differentiation, osteogenesis, and chondrogenesis. We compared the plasma concentrations of 134 miRNAs in 4 patients with trochanteric fractures and 4 healthy controls (HCs), and the levels of six miRNAs were dysregulated. Among these miRNAs, miR-92a levels were significantly decreased 24 hours after fracture, compared to HCs. In patients with a trochanteric fracture or a lumbar compression fracture, the plasma concentrations of miR-92a were lower on days 7 and 14, but had recovered on day 21 after the surgery or injury. To determine whether systemic downregulation of miR-92a can modulate fracture healing, we administered antimir-92a, designed using locked nucleic acid technology to inhibit miR-92a, to mice with a femoral fracture. Systemic administration of antimir-92a twice a week increased the callus volume and enhanced fracture healing. Enhancement of fracture healing was also observed after local administration of antimir-92a. Neovascularization was increased in mice treated with antimir-92a. These results suggest that plasma miR-92a plays a crucial role in bone fracture healing in human and that inhibition of miR-92a enhances fracture healing through angiogenesis and has therapeutic potential for bone repair.
microRNAs (miRNAs) 是内源性的小非编码 RNA，可调节靶 mRNA 的活性和细胞过程。虽然尚未有 miRNA 被报道在调节骨折愈合中发挥重要作用，但有几种 miRNA 控制着组织修复过程中的关键要素，如炎症、缺氧反应、血管生成、干细胞分化、成骨和软骨形成。我们比较了 4 例转子间骨折患者和 4 例健康对照者（HCs）的血浆中 134 种 miRNA 的浓度，发现其中 6 种 miRNA 表达失调。在这些 miRNA 中，miR-92a 的水平在骨折后 24 小时显著降低，与 HCs 相比。在转子间骨折或腰椎压缩性骨折患者中，miR-92a 的血浆浓度在第 7 天和第 14 天降低，但在手术后或受伤后第 21 天恢复正常。为了确定系统下调 miR-92a 是否能调节骨折愈合，我们用采用锁核酸技术设计的抗 miR-92a 处理股骨骨折的小鼠。每周两次全身给予抗 miR-92a 可增加骨痂体积并增强骨折愈合。局部给予抗 miR-92a 也观察到增强骨折愈合的作用。抗 miR-92a 处理的小鼠中血管新生增加。这些结果表明，血浆 miR-92a 在人类骨骨折愈合中起着至关重要的作用，抑制 miR-92a 通过血管生成增强骨折愈合，具有骨修复的治疗潜力。
