Grieco Giuseppina E, Cataldo Dorica, Ceccarelli Elena, Nigi Laura, Catalano Giovanna, Brusco Noemi, Mancarella Francesca, Ventriglia Giuliana, Fondelli Cecilia, Guarino Elisa, Crisci Isabella, Sebastiani Guido, Dotta Francesco
Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy.
Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, 53100, Italy.
Noncoding RNA. 2018 Nov 27;4(4):37. doi: 10.3390/ncrna4040037.
Type 1 diabetes (T1D) is characterized by bone loss and altered bone remodeling, resulting into reduction of bone mineral density (BMD) and increased risk of fractures. Identification of specific biomarkers and/or causative factors of diabetic bone fragility is of fundamental importance for an early detection of such alterations and to envisage appropriate therapeutic interventions. MicroRNAs (miRNAs) are small non-coding RNAs which negatively regulate genes expression. Of note, miRNAs can be secreted in biological fluids through their association with different cellular components and, in such context, they may represent both candidate biomarkers and/or mediators of bone metabolism alterations. Here, we aimed at identifying miRNAs differentially expressed in serum of T1D patients and potentially involved in bone loss in type 1 diabetes. We selected six miRNAs previously associated with T1D and bone metabolism: miR-21; miR-24; miR-27a; miR-148a; miR-214; and miR-375. Selected miRNAs were analyzed in sera of 15 T1D patients (age: 33.57 ± 8.17; BMI: 21.4 ± 1.65) and 14 non-diabetic subjects (age: 31.7 ± 8.2; BMI: 24.6 ± 4.34). Calcium, osteocalcin, parathormone (PTH), bone ALkaline Phoshatase (bALP), and Vitamin D (VitD) as well as main parameters of bone health were measured in each patient. We observed an increased expression of miR-148a ( 0.012) and miR-21-5p ( 0.034) in sera of T1D patients vs non-diabetic subjects. The correlation analysis between miRNAs expression and the main parameters of bone metabolism, showed a correlation between miR-148a and Bone Mineral Density (BMD) total body (TB) values ( 0.042) and PTH circulating levels ( 0.033) and the association of miR-21-5p to Bone Mineral Content-Femur (BMC-FEM). Finally, miR-148a and miR-21-5p target genes prediction analysis revealed several factors involved in bone development and remodeling, such as MAFB, WNT1, TGFB2, STAT3, or PDCD4, and the co-modulation of common pathways involved in bone homeostasis thus potentially assigning a role to both miR-148a and miR-21-5p in bone metabolism alterations. In conclusion, these results lead us to hypothesize a potential role for miR-148a and miR-21-5p in bone remodeling, thus representing potential biomarkers of bone fragility in T1D.
1型糖尿病（T1D）的特征是骨质流失和骨重塑改变，导致骨矿物质密度（BMD）降低以及骨折风险增加。识别糖尿病性骨脆性的特定生物标志物和/或致病因素对于早期检测此类改变并设想适当的治疗干预措施至关重要。微小RNA（miRNA）是一类小的非编码RNA，可负向调节基因表达。值得注意的是，miRNA可通过与不同细胞成分结合而分泌到生物体液中，在此背景下，它们可能代表骨代谢改变的候选生物标志物和/或介质。在此，我们旨在鉴定在T1D患者血清中差异表达且可能参与1型糖尿病骨质流失的miRNA。我们选择了先前与T1D和骨代谢相关的6种miRNA：miR-21；miR-24；miR-27a；miR-148a；miR-214；和miR-375。在15名T1D患者（年龄：33.57±8.17；体重指数：21.4±1.65）和14名非糖尿病受试者（年龄：31.7±8.2；体重指数：24.6±4.34）的血清中分析所选的miRNA。测量了每位患者的钙、骨钙素、甲状旁腺激素（PTH）、骨碱性磷酸酶（bALP）、维生素D（VitD）以及骨健康的主要参数。我们观察到，与非糖尿病受试者相比，T1D患者血清中miR-148a（0.012）和miR-21-5p（0.034）的表达增加。miRNA表达与骨代谢主要参数之间的相关性分析表明，miR-148a与全身骨矿物质密度（BMD）值（0.042）和循环PTH水平（0.033）之间存在相关性，以及miR-21-5p与股骨骨矿物质含量（BMC-FEM）之间存在相关性。最后，miR-148a和miR-21-5p靶基因预测分析揭示了几个参与骨发育和重塑的因素，如MAFB、WNT1、TGFB2、STAT3或PDCD4，以及参与骨稳态的共同途径的共调节，从而可能赋予miR-148a和miR-21-5p在骨代谢改变中的作用。总之，这些结果使我们推测miR-148a和miR-21-5p在骨重塑中具有潜在作用，因此代表T1D中骨脆性的潜在生物标志物。
