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Canagliflozin promotes osteoblastic MC3T3-E1 differentiation via AMPK/RUNX2 and improves bone microarchitecture in
Peiyang Song1, Tianyi Chen1, Shunli Rui1
1Department of Endocrinology, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China.
Abstract:
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 in vivo 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) in vitro. The level trend of RUNX2 and p-AMPK in vivo were consistent with those in vitro. 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.
Insights
Canagliflozin, a type 2 diabetes drug, improved bone health in mice by increasing bone mineral density and enhancing bone structure. This contrasts with other SGLT2 inhibitors, suggesting potential benefits for diabetic patients with fracture risks.
Area of Science:
- Endocrinology and Bone Metabolism
- Pharmacology of Diabetes Therapeutics
Background:
- Type 2 diabetes mellitus (T2DM) is linked to increased bone fracture risk.
- The impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on bone metabolism remains unclear.
- Existing T2DM treatments may affect bone health, necessitating investigation into drug-specific effects.
Purpose of the Study:
- To compare the effects of three SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) on bone metabolism in type 2 diabetic mice.
- To elucidate the underlying mechanisms by which SGLT2 inhibitors influence bone health.
- To identify potential therapeutic advantages of specific SGLT2 inhibitors for bone health in T2DM.
Main Methods:
- In vivo study using type 2 diabetic mouse models.
- Administration of canagliflozin, dapagliflozin, or empagliflozin to diabetic mice.
- Micro-computed tomography (micro-CT) analysis to assess bone microarchitecture and parameters.
- In vitro experiments to investigate the role of AMPK and RUNX2 in osteoblast differentiation.
Main Results:
- Canagliflozin significantly increased bone mineral density and improved bone microarchitecture in diabetic mice (p<0.05).
- Dapagliflozin and empagliflozin did not show significant improvements in bone parameters.
- Canagliflozin promoted osteoblast differentiation via the AMPK/RUNX2 pathway, confirmed by in vitro and in vivo analyses.
Conclusions:
- Canagliflozin demonstrates a beneficial effect on bone metabolism in type 2 diabetic mice, unlike dapagliflozin and empagliflozin.
- The findings suggest a potential role for canagliflozin in managing bone health in diabetic patients, particularly those at risk of osteoporosis or fracture.
- This study provides a mechanistic basis for canagliflozin's positive impact on bone, supporting its use in specific patient populations.
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