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

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.

Bone mineral density and markers of bone turnover and inflammation in diabetes patients with or without a Charcot foot: An 8.5-year prospective case-control study

“…Regarding the OPG levels, we did not find these altered between the groups at baseline or at follow-up, which does not correspond to the findings of Folestad et al (19) . It is possible that this is due to our low sample number.…”

“…Additionally, post surgery measurements show an increase which seems to peak after 2 months (44) . As shown by Folestad et al (19) , the RANK-L level for an acute Charcot foot is initially elevated, and continues to hold this level for 4 months.…”

“…Additionally, several recent studies have reported changes in biomarkers of bone resorption and inflammation in individuals with Charcot foot, specifically within the RANK/RANK-L/OPG system (14)(15)(16)(17)(18)(19) .…”

How We Manage Bone Marrow Edema—An Interdisciplinary Approach

“…The pathogenesis is largely unknown, but an unphysiological osteoclast to osteoblast ratio and an increased immuno-reactivity (IL1, IL6, TNF) have been shown [72]. Recent studies have focused on the RANK/RANK-L/OPG system [73,74]. The current treatment recommendations comprise extended immobilization and avoidance of weight-bearing activities in the affected leg for a duration of 3-12 months [72].…”

Corneal confocal microscopy detects severe small fiber neuropathy in diabetic patients with Charcot neuroarthropathy

“…Much of the focus has been on inflammatory pathways affecting osteoblast 7,8 and, more recently, osteoclast dysfunction 9,10 . Pathways that have received the most attention in the pathogenesis of CN include the receptor activator of nuclear factor-jB, receptor activator of nuclear factor-jB ligand and osteoprotegerin 11 , and more recently, abnormalities in sclerostin, dickkopf-1, Wnt inhibitory factor-1 and Wnt ligand-1 12 . The role of these pathways is complex, with a recent study showing initial suppression of receptor activator of nuclear factor-jB ligand in peripheral blood mononuclear cells followed by increased levels in those with faster healing on magnetic resonance imaging 13 .…”