Dysregulation of Wnt signaling in bone of type 2 diabetes mellitus and diabetic Charcot arthropathy

Laurens Christian Gassel, Sandra Schneider, Ingo Jörg Banke, Karl Friedrich Braun, Christoph Volkering, Leonie Zeeb, Rainer Hans Hermann Burgkart, Rüdiger von Eisenhart-Rothe, Peter Biberthaler, Martijn van Griensven, Alexander Tobias Haug*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Type 2 diabetes mellitus (T2DM) patients show a markedly higher fracture risk and impaired fracture healing when compared to non-diabetic patients. However in contrast to type 1 diabetes mellitus, bone mineral density in T2DM is known to be normal or even regionally elevated, also known as diabetic bone disease. Charcot arthropathy is a severe and challenging complication leading to bone destruction and mutilating bone deformities. Wnt signaling is involved in increasing bone mineral density, bone homeostasis and apoptotic processes. It has been shown that type 2 diabetes mellitus is strongly associated with gene variants of the Wnt signaling pathway, specifically polymorphisms of TCF7L2 (transcription factor 7 like 2), which is an effector transcription factor of this pathway. METHODS: Bone samples of 19 T2DM patients and 7 T2DM patients with additional Charcot arthropathy were compared to 19 non-diabetic controls. qPCR analysis for selected members of the Wnt-signaling pathway (WNT3A, WNT5A, catenin beta, TCF7L2) and bone gamma-carboxyglutamate (BGLAP, Osteocalcin) was performed and analyzed using the 2-Delta Delta Ct- Method. Statistical analysis comprised one-way analysis of variance (ANOVA). RESULTS: In T2DM patients who had developed Charcot arthropathy WNT3A and WNT5A gene expression was down-regulated by 89 and 58% compared to healthy controls (p < 0.0001). TCF7L2 gene expression showed a significant reduction by 63% (p < 0.0001) and 18% (p = 0.0136) in diabetic Charcot arthropathy. In all diabetic patients BGLAP (Osteocalcin) was significantly decreased by at least 59% (p = 0.0019). CONCLUSIONS: For the first time with this study downregulation of members of the Wnt-signaling pathway has been shown in the bone of diabetic patients with and without Charcot arthropathy. This may serve as future therapeutic target for this severe disease.
Original languageEnglish
Article number365
Number of pages10
JournalBMC Musculoskeletal Disorders
Volume23
Issue number1
DOIs
Publication statusPublished - 18 Apr 2022

Keywords

  • Diabetic bone disease
  • Type 2 diabetes mellitus
  • Wnt signaling
  • Osteocalcin
  • WNT/BETA-CATENIN
  • GENE-EXPRESSION
  • CONTROLS OSTEOBLAST
  • FRACTURE RISK
  • DIFFERENTIATION
  • CELL
  • OSTEOCALCIN
  • WOMEN
  • FOOT
  • MASS

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