Abstract:
The increased risk of fractures in patients with type 1 diabetes mellitus (T1DM) is nowadays well recognized. However, the exact mechanism of action of diabetic bone disease has not been fully elucidated. MicroRNAs (miRNAs) are gene regulators that operate post-transcriptionally and have been implicated in the development of various metabolic disorders including T1DM. Previous studies have implicated a role for miR-144-5p and miR-21-5p, which are involved in controlling oxidative stress by targeting Nrf2, in T1DM. To date, it is unclear whether miR-144-5p and miR-21-5p affect bone health in T1DM. Thus, this study aimed to investigate the influence of miR-144-5p and miR-21-5p knockdown in the development of bone disease in T1DM male mice. Therefore, T1DM was induced in 10-wk-old male mice using streptozotocin (STZ). One week later, after development of hyperglycemia, antagomir-144-5p and antagomir-21-5p or their non-targeting control were administered at 10 mg/kg BW once a week until the end of the experiment. At 14 wk of age, glucose levels, bone, and fat mass were analyzed. The results revealed that treating T1DM male mice with antagomir-144-5p and antagomir-21-5p did not protect against diabetes development or bone loss, despite the successful downregulation of the miRNAs and the normalization of Nrf2 mRNA levels in bone tissue. Histological and serological parameters of bone formation or resorption were not altered by the antagomir treatment. Finally, we measured the expression of miRNA-144-5p or miRNA-21-5p in the serum of 30 individuals with T1DM and compared them to non-diabetic controls, but did not find an altered expression of either miRNA. In conclusion, the knockdown of miR-144-5p and miR-21-5p does not affect STZ-induced diabetes development or loss of bone mass in male mice. However, it does normalize expression of the anti-oxidant factor Nrf2 in diabetic bone tissue.
摘要:
1型糖尿病(T1DM)患者的骨折风险增加是当今公认的。然而,糖尿病骨病的确切作用机制尚未完全阐明。MicroRNAs(miRNA)是转录后起作用的基因调节因子,并参与了包括T1DM在内的各种代谢紊乱的发展。先前的研究暗示了miR-144-5p和miR-21-5p的作用。在T1DM中,通过靶向Nrf2参与控制氧化应激。迄今为止,目前尚不清楚miR-144-5p和miR-21-5p是否影响T1DM患者的骨健康.因此,本研究旨在探讨miR-144-5p和miR-21-5p敲低在T1DM雄性小鼠骨病发生发展中的作用。因此,使用链脲佐菌素(STZ)在10周龄雄性小鼠中诱导T1DM。一周后,高血糖症发展后,antagomir-144-5p和antagomir-21-5p或它们的非靶向对照以10mg/kgBW每周施用一次,直到实验结束。14岁时,葡萄糖水平,骨头,和脂肪量进行了分析。结果显示,用antagomir-144-5p和antagomir-21-5p治疗T1DM雄性小鼠并不能预防糖尿病发展或骨丢失,尽管成功下调miRNAs和骨组织中Nrf2mRNA水平正常化。antagomir治疗未改变骨形成或吸收的组织学和血清学参数。最后,我们测量了30例T1DM患者血清中miRNA-144-5p或miRNA-21-5p的表达,并将其与非糖尿病对照进行了比较。但没有发现任何miRNA的表达改变。总之,miR-144-5p和miR-21-5p的敲低不影响STZ诱导的雄性小鼠的糖尿病发展或骨量丢失.然而,它确实使糖尿病骨组织中抗氧化因子Nrf2的表达正常化。