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Updated: Jan 15, 2026
A Zebrafish Model of Diabetes Mellitus and Metabolic Memory
Published on: February 28, 2013
BMDMs in metabolic memory impair fracture healing in diabetes
Dong Zhang1, Changjiang Liu2, Ying Yuan2
1Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. zhangdongemail@whu.edu.cn.
Background:
The risk of fractures nonunion and delayed union in diabetes mellitus remains elevated despite glucose-lowering therapies. We hypothesized that bone marrow-derived macrophages (BMDMs) can be induced in the status of metabolic memory and still impair fracture healing when hyperglycemia stimulus disappears.
Methods:
Diabetic mice were divided into control (Ctrl), diabetic (DM), and diabetic with glucose control (DM/GC) groups. Fracture healing was assessed by micro-CT and histology, evaluating callus volume, bone volume/total volume (BV/TV), and inflammatory markers. In vitro, bone marrow-derived macrophages (BMDMs) were exposed to high glucose (HG) for varying periods to simulate hyperglycemia-induced metabolic memory, followed by normalization. Pro-inflammatory cytokines and macrophage polarization (M1/M2) were assessed via ELISA and flow cytometry. Osteogenesis and angiogenesis were evaluated in co-culture assays. RNA-seq and ATAC-seq were performed to analyze gene expression and chromatin accessibility, focusing on inflammatory pathways and CEBPB.
Results:
All data show that BMDMs play a significant role in the sustained effects of hyperglycemia on fracture healing even after glucose normalization in diabetic animals. Hyperglycemia-induced metabolic memory in BMDMs resulted in increased pro-inflammatory cytokines and a higher proportion of M1 macrophages, which impaired osteogenesis and angiogenesis. The co-culture medium from BMDMs in metabolic memory conditions suppressed osteogenesis in BMSCs and angiogenesis in HUVECs. Integrated analysis of RNA-seq and ATAC-seq in BMDMs revealed that inflammatory pathways were upregulated, with CEBPB identified as a key factor. Silencing CEBPB reversed these adverse effects and enhanced fracture healing in a diabetic model.
Conclusions:
Our results demonstrate the reason why the glucose-lowering therapies is unsuccessful in reducing the risk of fractures nonunion and delayed union in patients with diabetes mellitus, and shed light on a new strategy for the disease.
Insights
Diabetes impairs fracture healing due to bone marrow-derived macrophages (BMDMs) retaining a pro-inflammatory memory. Targeting CEBPB in these macrophages can improve healing in diabetic individuals, offering a new therapeutic strategy.
Area of Science:
- Orthopedics
- Endocrinology
- Immunology
Background:
- Diabetes mellitus elevates fracture nonunion and delayed union risks, even with glucose control.
- Bone marrow-derived macrophages (BMDMs) may retain a 'metabolic memory' that impairs fracture healing post-hyperglycemia.
Purpose of the Study:
- To investigate the role of BMDM metabolic memory in impaired fracture healing in diabetes.
- To identify molecular mechanisms and potential therapeutic targets for improving fracture repair in diabetic patients.
Main Methods:
- Diabetic mice models with and without glucose control were used.
- Micro-CT, histology, ELISA, flow cytometry, co-culture assays, RNA-seq, and ATAC-seq were employed.
- In vitro studies simulated hyperglycemia-induced metabolic memory in BMDMs.
Main Results:
- Diabetic BMDMs exhibited enhanced pro-inflammatory (M1) polarization and cytokine release, impairing osteogenesis and angiogenesis.
- Metabolic memory in BMDMs persisted even after glucose normalization, negatively impacting fracture healing.
- CEBPB was identified as a key factor in inflammatory pathways; its silencing improved fracture healing in diabetic models.
Conclusions:
- BMDM metabolic memory explains the persistent risk of fracture complications in diabetes despite glucose-lowering therapies.
- Targeting CEBPB in BMDMs presents a novel therapeutic strategy for enhancing fracture healing in diabetes.
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