Dataset Information

Proteomic profiling of scaffold-guided bone healing in type 2 diabetes rat model with critical-sized bone defect

ABSTRACT: Type 2 diabetes mellitus significantly impairs bone healing, with delayed regeneration observed in over 60% of diabetic patients. This study investigated the molecular mechanisms underlying diabetes-associated compromised regeneration using time-resolved proteome profiling of critical-sized femoral defects in diabetic (Lepr-/-) and non-diabetic LundMetS rats treated with polycaprolactone scaffolds. Explanted regenerated callus and contralateral bone tissue were analyzed at 21- and 42-days post-surgery using TMT-based quantitative proteomics and functional enrichment analysis. Deep proteome coverage identified 4,384 proteins, revealing significantly reduced extracellular matrix proteins and elevated inflammatory proteins in diabetic defects at 42 days. A distinct mast cell protease cluster emerged as a novel mechanism, with diabetic callus containing 2.5-fold more mast cells and elevated tissue histamine. The findings demonstrate that diabetes converts physiological transient inflammatory processes into pathologically sustained networks through mast cell-neutrophil crosstalk, creating a self-reinforcing catabolic niche that prevents inflammatory resolution and matrix maturation.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Femur, Bone

DISEASE(S): Type 2 Diabetes Mellitus,Wounds And Injuries

SUBMITTER: Vivien Wiltzsch

LAB HEAD: Stefan Kalkhof

PROVIDER: PXD071312 | Pride | 2026-04-16

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	BiologicalSampleDescription.txt	Txt
	MSSampleDescription.txt	Txt
	Q1063095A8_20220927130024_20220824_CO_1063JoSc_R25_.raw	Raw
	Q1063096AG_20220927125248_20220824_CO_1063JoSc_R26_.raw	Raw
	Q1063097AO_20220927125311_20220824_CO_1063JoSc_R27_.raw	Raw

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Publications

Proteomic profiling links increased mast cell activity in regenerating callus to impaired scaffold-guided bone regeneration in diabetic rats.

Wiltzsch Vivien V Dias Daniela B DB Schmidt Johannes R JR Kirwan Jennifer A JA Lehmann Jörg J Poh Patrina S P PSP Kalkhof Stefan S

Bone 20260415

Type 2 diabetes mellitus significantly impairs bone healing, with delayed regeneration observed in over 60% of patients with diabetes. Using time-resolved proteome profiling of critical-sized femoral defects in diabetic and non-diabetic rats treated with polycaprolactone scaffolds, we investigated the molecular mechanisms underlying diabetes-associated compromised regeneration. Explanted regenerated callus and contralateral bone tissue were analyzed at 21 and 42 days post-surgery using mass spec ...[more]

PMID: 41990899

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Project description:Background—Diabetes is a prevalent public health problem that affects about one third of the U.S. population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes complications is incompletely understood. We thus investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. Methods and Results—In three types of mouse diabetes, we observed enhanced proliferation of hematopoietic stem and progenitor cells (HSPC) leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (EGFR) signaling in mice with diet-induced diabetes. To explore whether endothelial EGFR plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of EGFR (Cdh5Cre EGFRfl/fl). Unexpectedly, we found enhanced HSPC proliferation and increased myeloid cell production in Cdh5Cre EGFRfl/fl mice compared to wild type mice with diabetes. Disrupted EGFR signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5Cre EGFRfl/fl mice, significantly delaying wound closure. Atherosclerosis accelerated in Cdh5Cre EGFRfl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta. Conclusions—In diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis and promote cardiovascular complications via leukocyte overproduction. Specifically, diabetes reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We also describe a previously unknown counter-regulatory pathway, in which protective endothelial EGFR signaling curbs HSPC proliferation and myeloid cell production via angiopoietin-1.