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.

The primary peak of proinflammatory cytokines involved in the initiation of bone healing after trauma is in line with previous results. The primary phase of increased matrix proteins, P1NP and BALP paralleled by RANKL, OPG and Wnt/β-catenin remaining at preoperative level until 5Y, support a strong formation of mineralized matrix and to a lesser degree bone during this phase. The secondary proinflammatory peak at 5Y is likely a trigger of coupled bone remodeling and neosynthesis as it is followed by increased levels of the bone anabolic turnover marker, BALP, and mediators of the RANKL/OPG and Wnt/β-catenin pathways. A continuous increase by OPG level and the bone turnover marker, BALP, lasting from 5Y until 18Y and paralleled by a similar decrease in sclerostin level support their being key regulators of bone anabolism, whereas the transient and opposed activities of RANKL, Wnt-1, Dkk-1 and sFRP-1 serve as fine tuning tools during the coupled remodeling phase.

BackgroundLittle is currently known of the pathophysiological mechanisms triggering Charcot arthropathy and regulating its recovery although foot trauma has been proposed as a major initiating factor by activation of proinflammatory cytokines leading to increased osteoclastogenic activity and progressive bone destruction. Several members of the IL-17 family of proinflammatory cytokines have been shown to play a key role in the pathogenesis of inflammatory conditions affecting bone and joints but none has previously been studied in Charcot foot patients. The aim of this study was to investigate the role of IL-17A, IL-17E and IL-17F in patients presenting with Charcot foot.MethodsTwenty-six consecutive Charcot patients were monitored during 2 years by repeated foot radiographs, MRI and circulating levels of IL-17A, IL-17E and IL-17F. Analysis of cytokines was done by ultra-sensitive chemiluminescence technique and data were analyzed by one-way repeated measures ANOVA. Neuropathic diabetic patients (n = 20) and healthy subjects (n = 20) served as controls.ResultsPlasma IL-17A and IL-17E in weight-bearing Charcot patients at diagnosis were at the level of diabetic controls, whereas IL-17F was significantly lower than diabetic controls. A significant increase in IL-17A and IL-17E reaching a peak 2–4 months after inclusion and start of offloading treatment in Charcot patients was followed by a gradual decrease to the level of diabetic controls at 2 years postinclusion. In contrast, IL-17F increased gradually from inclusion to a level not significantly different from diabetic controls after 2 years.ConclusionsCharcot patients display a significant elevation of all three IL-17 cytokines during the follow-up period relative values at diagnosis and values in control patients supporting a role in the bone repair and remodeling activity during the recovery phase. The rapid increase of IL-17A and IL-17E shortly after initiating off-loading treatment could suggest this to be a response to immobilization and stabilization of the diseased foot.

BackgroundProinflammatory cytokines are an integral part of the osteolytic activity of Charcot arthropathy but are also central to normal bone healing. As there are no previous longitudinal studies investigating their role during the recovery phase of Charcot, we set out to monitor systemic levels of proinflammatory cytokines from Charcot presentation until a clinically and radiographically documented chronic state has been reached.MethodsTwenty-eight consecutive Charcot patients were monitored during 2 years by repeated foot radiographs, MRI and plasma levels of interleukin [IL]-6, IL-8, IL-1β, Tumor Necrosis Factor [TNF]-α, and IL-1 receptor antibody (IL-1RA). Charcot patients were treated with total contact cast (TCC) on the first day of inclusion. Neuropathic diabetic controls (n = 20) and Healthy subjects (n = 20) served as reference.ResultsPlasma IL-6, IL-8, IL-1β and TNF-α in the acute and chronic phase of Charcot were below or at the level of diabetic controls and healthy, whereas IL-1RA/IL-1β ratio was continuously higher in Charcot patients. IL-6, TNF-α and IL-1RA began to increase one week after offloading to reach a peak after 4 months before gradually receding.ConclusionsA sustained increase of IL-6 and TNF-α starting shortly after offloading and paralleled by accelerated bone healing on radiographs, suggest that offloading, by activating the inflammatory stage, has a key role to play in the onset of coupled bone remodeling. High IL-1RA/IL-1β ratio in Charcot patients at presentation supports a counter-balancing anti-inflammatory role for IL-1RA in the acute phase whereas a high ratio after two years, possibly due to renewed weight-bearing on a deformed foot, signal need for continued anti-inflammatory activity and contradicts a “cold” biological state in the chronic phase.

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