Abstract
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.
Highlights
Little is currently known of the pathophysiological mechanisms triggering Charcot arthropathy and regulating its recovery foot trauma has been proposed as a major initiating factor by activation of proinflammatory cytokines leading to increased osteoclastogenic activity and progressive bone destruction
Despite decade-long dominant role assigned to the proinflammatory cytokines belonging to the T-helper 1 and T-helper 2 cell (Th1/Th2) subsets of the immune system (e.g. IL-6, IL-1β and TNF-α) as the driving force for the development and maintenance of inflammationdriven bone- and joint diseases [6], it is evident that T-helper 1 and T-helper cell (Th1/Th2) cannot alone account for the pathogenesis of these disorders [7] and that many inflammatory conditions are partly or largely driven by a new subset, namely the T-helper 17 (Th17) cells [8], which are the main source of IL-17 cytokines
IL-17E was significantly higher in Charcot patients versus diabetic controls (p = 0.021) and versus healthy subjects (p = 0.002) but did not differ significantly between diabetic controls and healthy (p = 0.32) (Fig. 2a)
Summary
Little is currently known of the pathophysiological mechanisms triggering Charcot arthropathy and regulating its recovery foot trauma has been proposed as a major initiating factor by activation of proinflammatory cytokines leading to increased osteoclastogenic activity and progressive bone destruction. Despite decade-long dominant role assigned to the proinflammatory cytokines belonging to the T-helper 1 and T-helper 2 cell (Th1/Th2) subsets of the immune system (e.g. IL-6, IL-1β and TNF-α) as the driving force for the development and maintenance of inflammationdriven bone- and joint diseases [6], it is evident that Th1/Th2 cannot alone account for the pathogenesis of these disorders [7] and that many inflammatory conditions are partly or largely driven by a new subset, namely the T-helper 17 (Th17) cells [8], which are the main source of IL-17 cytokines This family is composed of six members ranging from IL-17A to IL-17F which exert their biological actions through activation of several cascade systems, such as NFκB and kinase signaling pathways [9]. Despite Charcot arthropathy being a bone degenerative condition, we are not aware of any study investigating the role of this important family of proinflammatory cytokines in Charcot patients
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