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. 2020 Jun 5:20:459-467.
doi: 10.1016/j.omtn.2020.03.010. Epub 2020 Mar 29.

miR-26a Attenuated Bone-Specific Insulin Resistance and Bone Quality in Diabetic Mice

Fusong Jiang  1 , Yang Zong  2 , Xin Ma  2 , Chaolai Jiang  2 , Haojie Shan  2 , Yiwei Lin  2 , Wenyang Xia  2 , Fuli Yin  2 , Nan Wang  3 , Lihui Zhou  4 , Zubin Zhou  5 , Xiaowei Yu  6
Affiliations

miR-26a Attenuated Bone-Specific Insulin Resistance and Bone Quality in Diabetic Mice

Fusong Jiang et al. Mol Ther Nucleic Acids. .

Abstract

Diabetes mellitus is a prevalent disease result in several complications, including bone problems. Previous studies have shown that microRNA (miR)-26a regulates glucose metabolism and plays a protective role in diabetes. However, whether miR-26a also affects bone quality in diabetes remains unknown. In the present study, we evaluated the potential effects of miR-26a on bone in diabetic mice. We administrated miR-26a in streptozotocin-induced diabetic mice. The metabolic parameters, bone quality, osteoblast and osteoclast markers, and insulin signaling activation were measured. miR-26a ameliorated insulin resistance and glucose tolerance, improved bone microarchitecture and quality, increased osteoblasts and bone formation, decreased osteoclasts, and promoted the insulin signaling pathway in diabetic mice. These effects were abolished in insulin receptor-compromised Col1a1-Insr+/- mice. In conclusion, miR-26a could ameliorate bone-specific insulin resistance and bone quality in diabetic mice, which depended on the insulin receptors on osteoblasts. Our findings highlight the potential of miR-26a as a therapeutic target for diabetes mellitus-related bone metabolism and diseases.

Keywords: bone; diabetes; insulin receptor; miR-26a.

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Figures

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Graphical abstract
Figure 1
Figure 1
miR-26a Mimics Prevent Insulin Resistance and Glucose Tolerance in Diabetic Mice (A) Total body weight, (B) blood glucose, (C) GTT, (D) blood insulin, and (E) ITT, performed after 18 weeks of STZ. Data are shown as mean ± SD. n = 8 mice, ∗p < 0.05; ∗∗p < 0.01 compared with STZ group.
Figure 2
Figure 2
Effect of miR-26a Mimics on Trabecular Bone Microarchitecture in Distal Femora and Cortical Bone Thickness of Diabetic Mice (A) Bone volume per tissue volume (BV/TV), (B) trabecular number (Tb.N), (C) trabecular thickness (Tb.Th), (D) trabecular separation (Tb.Sp), (E) cortical thickness (Ct.Th), and (F) cortical area (Ct.Th). Data are shown as mean ± SD. n = 8 mice, ∗p < 0.05; ∗∗p < 0.01 compared with STZ group.
Figure 3
Figure 3
miR-26a Mimics Increased Osteoblasts and Bone Formation and Decreased Osteoclasts in Diabetic Mice (A) Number of osteoblasts per bone surface (NOb/BS), (B) surface covered by osteoblasts (ObS/BS), (C) osteoid surface (OS/BS), (D) osteoclast number per bone surface (NOc/BS), (E) surface covered by osteoclasts (OcS/BS), (F) eroded surface per bone surface (ES/BS), (G) mineralizing surface (MS/BS), (H) mineral apposition rate (MAR), and (I) bone formation rate (BFR/BS). Data are shown as mean ± SD. n = 8 mice, ∗p < 0.05; ∗∗p < 0.01 compared with STZ group.
Figure 4
Figure 4
Effect of miR-26a Mimics on Bone Resorption and Formation Markers and Bone Gene Expression Induced by STZ (A) C-telopeptide fragments of type I collagen (CTX) and (B) osteocalcin (OCN) measured at the end of the study in serum and plasma, respectively. (C–H) Expression of the osteoblast marker osterix (C) and the cytokines OPG (D) and RANKL (E), the osteoclast marker TRAP (F), and the Wnt/β-catenin antagonists, Sost (G) and Dkk1 (H), in tibia. Data are shown as mean ± SD. n = 8 mice, ∗∗p < 0.01 compared with STZ group.
Figure 5
Figure 5
Effect of miR-26a Mimics on Insulin Signaling Induced by STZ (A) Western blot analysis of the phosphorylation levels of INSR and AKT in bones. (B–D) Relative protein levels compared with the control (Ctrl) group. Data are shown as mean ± SD. n = 8 mice, ∗∗p < 0.01 compared with STZ group.
Figure 6
Figure 6
Effect of miR-26a Mimics on Insulin Resistance and Glucose Tolerance Was Blocked in Col1a1-Insr+/− STZ Mice (A) Total body weight, (B) blood glucose, (C) GTT, (D) blood insulin, and (E) ITT performed after 18 weeks of STZ. Data are shown as mean ± SD. n = 8 mice. ∗∗p < 0.01. NS, no significance.
Figure 7
Figure 7
Effect of miR-26a Mimics on Trabecular Bone Microarchitecture in Distal Femora and Cortical Bone Thickness Was Blocked in Col1a1-Insr+/− STZ Mice (A) Bone volume per tissue volume (BV/TV), (B) trabecular number (Tb.N), (C) trabecular thickness (Tb.Th), (D) trabecular separation (Tb.Sp), (E) cortical thickness (Ct.Th), and (F) cortical area (Ct.Ar). Data are shown as mean ± SD. n = 8 mice. ∗∗p < 0.01. NS, no significance.
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