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

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-ΔΔCt- 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.

Pathophysiology of Bone and Mineral Metabolism

“…Normally, Wnt ligands bind to one of the frizzled family receptors (FZD) and to a co-receptor low-density lipoprotein receptor-related protein (LRP) to activate b-catenin dependent pathway (canonical signaling) and subsequent bone formation (81,82). Conversely, Wnt signal transduction seems to be redundant in both obesity (83) and T2DM (84). Previous studies showed a close relationship between upregulation of classical Wnt signaling and enhanced myogenesis and/or osteogenesis (85,86).…”

The complex pathophysiology of bone fragility in obesity and type 2 diabetes mellitus: therapeutic targets to promote osteogenesis

“…Normally, Wnt ligands bind to one of the frizzled family receptors (FZD) and to a co-receptor low-density lipoprotein receptor-related protein (LRP) to activate β-catenin dependent pathway (canonical signaling) and subsequent bone formation ( 81 , 82 ). Conversely, Wnt signal transduction seems to be redundant in both obesity ( 83 ) and T2DM ( 84 ). Previous studies showed a close relationship between upregulation of classical Wnt signaling and enhanced myogenesis and/or osteogenesis ( 85 , 86 ).…”

High-Intensity Interval Cycling and Running Yield a Similar Myokine and Osteokine Response in Young Adult Females

“…Osteocalcin is a non-collagenous protein released by osteoblasts that plays an important role in calcium metabolism, bone mineralization, and energy homeostasis [19,20] and has been used as a marker of the overall anabolic effects of exercise on bone metabolism. While some studies have reported an increase in total osteocalcin levels immediately and 3 h after a single bout of high-intensity interval exercise in female participants [21], a recent study of young adult males performing two moderate-intensity exercise trials on a cycle ergometer and on a treadmill found no changes in osteocalcin up to 1 h following either trial [22].…”