Canagliflozin promotes osteoblastic MC3T3-E1 differentiation via AMPK/RUNX2 and improves bone microarchitecture in type 2 diabetic mice

• Published in: Frontiers in endocrinology (Lausanne) Vol. 13; p. 1081039
• Main Authors: Song, Peiyang, Chen, Tianyi, Rui, Shunli, Duan, Xiaodong, Deng, Bo, Armstrong, David G, Ma, Yu, Deng, Wuquan
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 16.12.2022
• Subjects: Adenosine Monophosphate - therapeutic use; AMP-Activated Protein Kinases - metabolism; AMPK/RUNX2; Animals; Bone Diseases, Metabolic - drug therapy; bone metabolism; canagliflozin; Canagliflozin - pharmacology; Canagliflozin - therapeutic use; Core Binding Factor Alpha 1 Subunit; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Endocrinology; Glucose - therapeutic use; Mice; SGLT2 inhibitors; type 2 diabetes mellitus; type 2 diabetes mellitus; bone metabolism; AMPK/RUNX2; canagliflozin; SGLT2 inhibitors
• ISSN: 1664-2392; 1664-2392
• DOI: 10.3389/fendo.2022.1081039

Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone metabolic disorders and bone fracture due to disease progression and clinical treatment. The effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors, now greatly prescribed for the treatment of T2DM, on bone metabolism is not clear. This study aimed to explore the possible influence of bone metabolic disorder and the underlying mechanism through a comparison of three different SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) in the treatment of type 2 diabetic mice. For the experiments, four groups (DM, DM+Cana, DM+Dapa, and DM+Empa) were established using micro-CT to detect the bone microarchitecture and bone-related parameters. The study results indicated that canagliflozin, but not dapagliflozin or empagliflozin, increased bone mineral density (p<0.05) and improved bone microarchitecture in type 2 diabetic mice. Furthermore, canagliflozin promoted osteoblast differentiation at a concentration of 5 μM under high glucose concentration (HG). Phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) α (Thr172) has been confirmed to activate run-related transcription factor-2 (RUNX2) to perform this function. This effect can be partially reversed by the AMPK inhibitor dorsomorphin (compound C) and strengthened by the AMPK activator acadesine (AICAR) . The level trend of RUNX2 and p-AMPK were consistent with those This study suggested that canagliflozin played a beneficial role in bone metabolism in type 2 diabetic mice compared with dapagliflozin and empagliflozin. It provides some theoretical support for the chosen drugs, especially for patients with osteoporosis or a high risk of fracture.