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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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BMDMs in metabolic memory impair fracture healing in diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Dong Zhang,
  • Changjiang Liu,
  • Ying Yuan,
  • Junwei Su,
  • Zheng Wang,
  • Chao Jian,
  • Aixi Yu

摘要

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.