Charcot Pathogenesis: A Study of In Vivo Gene Expression

Connors, James C.; Hardy, Mark A.; Kishman, Lauren L.; Botek, Georgeanne; Verdin, Craig; Rao, Nilin M; Kingsley, J. Derek

doi:10.1053/j.jfas.2018.03.023

Cited by 11 publications

(7 citation statements)

References 29 publications

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“…Surgery in Charcot arthropathy is conducted in very few specialized centers only, which moreover narrows the pool of possible sample donors. Nevertheless, our sample size is in line with studies on this special field of research [ 36 , 47 , 56 ].…”

Section: Discussionmentioning

confidence: 62%

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

Gassel

Schneider

Banke

et al. 2022

BMC Musculoskelet Disord

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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.

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Section: Discussionmentioning

confidence: 62%

“…Both molecules have inhibitory effects on Wnt signaling [ 36 ]. Other studies do not confirm these findings in peripheral blood [ 47 ]. Bruhn-Olszewska et al showed a correlation between single nucleotide polymorphisms of OPG and Charcot arthropathy [ 48 ].…”

Section: Discussionmentioning

confidence: 75%

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

Gassel

Schneider

Banke

et al. 2022

BMC Musculoskelet Disord

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“…In particular, previous studies on bone metabolism revealed enhanced osteoclastic activity, instead of osteoblastic activity, in acute and chronic CN patients ( Jeffcoate, 2005 ). Furthermore, inflammatory cytokines such as IL-1β and IL-6 are found to be highly involved in the pathogenesis of CN through induction of nuclear factor kappa B (NF-κB) and RANKL activities ( Connors et al, 2018 ). Although some studies reported that there was no significant difference in the ratio of RANKL/OPG between CN patients and participants without CN ( Connors et al, 2018 ), in vitro and in vivo results have proposed the importance of this system in the development of CN ( Geusens et al, 2006 ).…”

Section: Regulatory Factors In the Development Of Cnmentioning

confidence: 99%

Therapeutics of Charcot neuroarthropathy and pharmacological mechanisms: A bone metabolism perspective

et al. 2023

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Charcot neuroarthropathy (CN) is a chronic, destructive, and painless damage of the skeletal system that affects the life quality of patients. CN, with an unclear mechanism, is characterized with invasive destruction of bones and a serious abnormality of bone metabolism. Unfortunately, development of an effective prevention and treatment strategy for CN is still a great challenge. Of note, recent studies providing an insight into the molecular mechanisms of bone metabolism and homeostasis have propelled development of novel CN therapeutic strategies. Therefore, this review aims to shed light on the pathogenesis, diagnosis, and treatment of CN. In particular, we highlight the eminent role of the osteoprotegerin (OPG)-receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL) system in the development of CN. Furthermore, we summarize and discuss the diagnostic biomarkers of CN as well as the potential pharmacological mechanisms of current treatment regimens from the perspective of bone metabolism. We believe that this review will enhance the current state of knowledge on the diagnosis, prevention, and therapeutic efficacy of CN.

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“…We read with interest the article by Connors et al (1) titled "Charcot Pathogenesis: A Study of In Vivo Gene Expression," and we want to add our findings about Charcot neuropathic osteoarthropathy (CN). Our findings might help new research into Charcot pathogenesis.…”

mentioning

confidence: 99%

“…Evidence of soft tissue enhancement was observed in 10 patients, and all extremities showing this sign have CN. Zhang et al (1) showed that soft tissue enhancement in patients with diabetes might be indicative of potential ulcer or cellulitis development. However, we found no information in the literature concerning CN in relation to soft tissue enhancement on MR imaging.…”

mentioning

confidence: 99%

Charcot Neuroarthropathy and a New Sign: “Soft Tissue Contamination Sign of Foot or Ankle” on Bolus Chase 3-Dimensional Magnetic Resonance Imaging

Çildağ

Ertuğrul

Köseoğlu

2020

The Journal of Foot and Ankle Surgery

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Charcot Pathogenesis: A Study of In Vivo Gene Expression

Cited by 11 publications

References 29 publications

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

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

Therapeutics of Charcot neuroarthropathy and pharmacological mechanisms: A bone metabolism perspective

Charcot Neuroarthropathy and a New Sign: “Soft Tissue Contamination Sign of Foot or Ankle” on Bolus Chase 3-Dimensional Magnetic Resonance Imaging

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