Metformin regulates bone marrow stromal cells to accelerate bone healing in diabetic mice
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eLife assessment
This fundamental work advances our understanding of the effects of metformin on bone healing in hyperglycemic conditions. The evidence supporting the conclusion is convincing, using three different types of bone fracture models in type-2 diabetes (T2D) mice. This paper is of potential interest to skeletal biologists, orthopaedic surgeons, and endocrinologists who study the effects of metformin on fracture healing.
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Abstract
Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.
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eLife assessment
This fundamental work advances our understanding of the effects of metformin on bone healing in hyperglycemic conditions. The evidence supporting the conclusion is convincing, using three different types of bone fracture models in type-2 diabetes (T2D) mice. This paper is of potential interest to skeletal biologists, orthopaedic surgeons, and endocrinologists who study the effects of metformin on fracture healing.
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Reviewer #1 (Public Review):
Guo et al. demonstrate that Metformin, a first-line anti-diabetic drug, significantly improves bone healing in diabetic mice. Mechanistically, they demonstrate that Metformin improves BMSC differentiation in T2D type 2 diabetic mice, potentially through an indirect mechanism. Overall the study is comprehensive and the effects of Metformin on bone healing are demonstrated by overwhelming data. The study further offers important information for management of the complications associated with type-2 diabetes. The weakness of the study is the lack of in-depth understanding of the mechanism underlying Metformin's effects on healing. The writing of the manuscript could also be improved for clarity and accuracy.
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Reviewer #2 (Public Review):
Diabetes mellitus is a worldwide public health menace, and the fracture healing is usually impaired in diabetic patients. Metformin is the first-line medicine for type-2 diabetes (T2D). However, its effects on bone in T2D patients remain unclear. To assess the impacts of metformin on fracture healing, the authors study the healing process after injuries caused by three different types of bone fractures in diabetic mouse models with or without metformin treatment. The authors studied three fracture models and looked at various aspects of the bone healing process and concluded that metformin rescues the delayed bone healing and remodeling in T2D mice. Moreover, the authors present novel information on the impact of metformin on the bone proliferation, bone formation, and cartilage formation in the bone marrow …
Reviewer #2 (Public Review):
Diabetes mellitus is a worldwide public health menace, and the fracture healing is usually impaired in diabetic patients. Metformin is the first-line medicine for type-2 diabetes (T2D). However, its effects on bone in T2D patients remain unclear. To assess the impacts of metformin on fracture healing, the authors study the healing process after injuries caused by three different types of bone fractures in diabetic mouse models with or without metformin treatment. The authors studied three fracture models and looked at various aspects of the bone healing process and concluded that metformin rescues the delayed bone healing and remodeling in T2D mice. Moreover, the authors present novel information on the impact of metformin on the bone proliferation, bone formation, and cartilage formation in the bone marrow stromal cells (BMSCs) derived from T2D mice. Administration of metformin in T2D mice can rescue the impaired differentiation potential and lineage commitment of BMSCs both in vitro and in vivo, compromised by the hyperglycemic conditions. In addition, several key chondrocyte transcript factors such as SOX9 and PGC1α, are upregulated in callus tissue isolated at the fracture site of metformin-treated diabetic mice during the healing process after the fracture. In summary, the authors present convincing evidence that metformin facilitates bone healing, bone formation and chondrogenesis in diabetic mice. The prior literature has focused on the effects on mesenchymal stem cells (MSCs) and this paper's data is novel as it's using MKR models for studying Metformin 's role in bone formation under diabetes condition. The paper's conclusions and results are strong, but more attention needs to be paid to the introduction and description of the prior literature and understanding of the potential specific targets and signaling pathway of metformin in the MKR mouse model bone healing.
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Reviewer #3 (Public Review):
The authors, in their research manuscript, dissected the role of Metformin in bone healing under type-2 diabetics conditions. The authors used three classic bone fracture models to assess the impacts of Metformin in bone healing under hyperglycemic conditions. In all three models, Metformin treatment showed bone formation. At the cellular level, the authors showed the effect of Metformin on promoting bone healing using BMSCs in vitro. The authors in the paper demonstrated that Metformin promotes bone growth only in hyperglycemic conditions. The experiments were appropriately well-defined and carried out to support the role of Metformin in bone healing. The use of three different bone-defective rat models to study the role of Metformin in skeletal tissues is convincing.
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