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Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients.

Folestad A, Ålund M, Asteberg S, Fowelin J, Aurell Y, Göthlin J, Cassuto J - Acta Orthop (2015)

Bottom Line: Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups.OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years.This is of particular clinical relevance considering the recent emergence of promising drugs that target this system.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopedic Surgery, CapioLundby Hospital , Göteborg.

ABSTRACT

Background and purpose: Charcot neuropathy is characterized by bone destruction in a foot leading to deformity, instability, and risk of amputation. Little is known about the pathogenic mechanisms. We hypothesized that the bone-regulating Wnt/β-catenin and RANKL/OPG pathways have a role in Charcot arthropathy.

Patients and methods: 24 consecutive Charcot patients were treated by off-loading, and monitored for 2 years by repeated foot radiography, MRI, and circulating levels of sclerostin, dickkopf-1, Wnt inhibitory factor-1, Wnt ligand-1, OPG, and RANKL. 20 neuropathic diabetic controls and 20 healthy controls served as the reference.

Results: Levels of sclerostin, Dkk-1 and Wnt-1, but not of Wif-1, were significantly lower in Charcot patients than in the diabetic controls at inclusion. Dkk-1 and Wnt-1 levels responded to off-loading by increasing. Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups. OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years. OPG/RANKL ratio was balanced in all groups at inclusion, and it remained balanced in Charcot patients on repeated measurement throughout the study.

Interpretation: High plasma RANKL and OPG levels at diagnosis of Charcot suggest that there is high bone remodeling activity before gradually normalizing after off-loading treatment. The consistently balanced OPG/RANKL ratio in Charcot patients suggests that there is low-key net bone building activity by this pathway following diagnosis and treatment. Inter-group differences at diagnosis and changes in Wnt signaling following off-loading treatment were sufficiently large to be reflected by systemic levels, indicating that this pathway has a role in bone remodeling and bone repair activity in Charcot patients. This is of particular clinical relevance considering the recent emergence of promising drugs that target this system.

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Related in: MedlinePlus

A and B. Box plots of plasma Dickkopf-1 (Dkk-1, pg/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B). C. Trajectory of plasma Dkk-1 in Charcot patients throughout the observation period of 2 years, based on repeated sampling over time and relative to diabetic controls and healthy subjects. Mean (SEM). a p = 0.009 for Charcot patients at 4 months vs. Charcot patients at inclusion; b p = 0.01 for Charcot patients at 2 years vs. Charcot patients at inclusion, as analyzed by Mann-Whitney rank sum test.
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Figure 6: A and B. Box plots of plasma Dickkopf-1 (Dkk-1, pg/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B). C. Trajectory of plasma Dkk-1 in Charcot patients throughout the observation period of 2 years, based on repeated sampling over time and relative to diabetic controls and healthy subjects. Mean (SEM). a p = 0.009 for Charcot patients at 4 months vs. Charcot patients at inclusion; b p = 0.01 for Charcot patients at 2 years vs. Charcot patients at inclusion, as analyzed by Mann-Whitney rank sum test.

Mentions: Clinical and demographic data are presented in Table 1. In Figures 4, 5C, 6C, 7C, and 8C, the results are given as linear graphs representing repeated measurements of individual biomarkers ranging over the entire period of observation from inclusion until 2 years after inclusion. In the other figure panels, the box plots illustrate inter-group comparisons at inclusion and 2 years after inclusion with the median represented by the horizontal line within the box, the 25th and 75th percentiles represented by the box, the 5th and 95th percentiles represented by the whiskers, and outliers represented by dots.


Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients.

Folestad A, Ålund M, Asteberg S, Fowelin J, Aurell Y, Göthlin J, Cassuto J - Acta Orthop (2015)

A and B. Box plots of plasma Dickkopf-1 (Dkk-1, pg/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B). C. Trajectory of plasma Dkk-1 in Charcot patients throughout the observation period of 2 years, based on repeated sampling over time and relative to diabetic controls and healthy subjects. Mean (SEM). a p = 0.009 for Charcot patients at 4 months vs. Charcot patients at inclusion; b p = 0.01 for Charcot patients at 2 years vs. Charcot patients at inclusion, as analyzed by Mann-Whitney rank sum test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4513595&req=5

Figure 6: A and B. Box plots of plasma Dickkopf-1 (Dkk-1, pg/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B). C. Trajectory of plasma Dkk-1 in Charcot patients throughout the observation period of 2 years, based on repeated sampling over time and relative to diabetic controls and healthy subjects. Mean (SEM). a p = 0.009 for Charcot patients at 4 months vs. Charcot patients at inclusion; b p = 0.01 for Charcot patients at 2 years vs. Charcot patients at inclusion, as analyzed by Mann-Whitney rank sum test.
Mentions: Clinical and demographic data are presented in Table 1. In Figures 4, 5C, 6C, 7C, and 8C, the results are given as linear graphs representing repeated measurements of individual biomarkers ranging over the entire period of observation from inclusion until 2 years after inclusion. In the other figure panels, the box plots illustrate inter-group comparisons at inclusion and 2 years after inclusion with the median represented by the horizontal line within the box, the 25th and 75th percentiles represented by the box, the 5th and 95th percentiles represented by the whiskers, and outliers represented by dots.

Bottom Line: Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups.OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years.This is of particular clinical relevance considering the recent emergence of promising drugs that target this system.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopedic Surgery, CapioLundby Hospital , Göteborg.

ABSTRACT

Background and purpose: Charcot neuropathy is characterized by bone destruction in a foot leading to deformity, instability, and risk of amputation. Little is known about the pathogenic mechanisms. We hypothesized that the bone-regulating Wnt/β-catenin and RANKL/OPG pathways have a role in Charcot arthropathy.

Patients and methods: 24 consecutive Charcot patients were treated by off-loading, and monitored for 2 years by repeated foot radiography, MRI, and circulating levels of sclerostin, dickkopf-1, Wnt inhibitory factor-1, Wnt ligand-1, OPG, and RANKL. 20 neuropathic diabetic controls and 20 healthy controls served as the reference.

Results: Levels of sclerostin, Dkk-1 and Wnt-1, but not of Wif-1, were significantly lower in Charcot patients than in the diabetic controls at inclusion. Dkk-1 and Wnt-1 levels responded to off-loading by increasing. Sclerostin levels were significantly higher in the diabetic controls than in the other groups whereas Wif-1 levels were significantly higher in the healthy controls than in the other groups. OPG and RANKL levels were significantly higher in the Charcot patients than in the other groups at inclusion, but decreased to the levels in healthy controls at 2 years. OPG/RANKL ratio was balanced in all groups at inclusion, and it remained balanced in Charcot patients on repeated measurement throughout the study.

Interpretation: High plasma RANKL and OPG levels at diagnosis of Charcot suggest that there is high bone remodeling activity before gradually normalizing after off-loading treatment. The consistently balanced OPG/RANKL ratio in Charcot patients suggests that there is low-key net bone building activity by this pathway following diagnosis and treatment. Inter-group differences at diagnosis and changes in Wnt signaling following off-loading treatment were sufficiently large to be reflected by systemic levels, indicating that this pathway has a role in bone remodeling and bone repair activity in Charcot patients. This is of particular clinical relevance considering the recent emergence of promising drugs that target this system.

Show MeSH
Related in: MedlinePlus