IL‐17 cytokines in bone healing of diabetic Charcot arthropathy patients: a prospective 2 year follow‐up study

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.

Offloading treatment is linked to activation of proinflammatory cytokines and start of bone repair and remodeling in Charcot arthropathy patients

“…Such a mechanism could explain the current results showing that IL-6 and TNF-α had begun to increase shortly after TCC treatment when unfavorable healing conditions caused by continued weight-bearing on the diseased foot had ceased. A similar increase by IL-17 family cytokines shortly after TCC in Charcot patients [ 12 ] lend further support to offloading being a critical factor which interrupts the vicious cycle caused by continued weight-bearing and sets the wheels of bone repair in motion. Although it may seem paradoxical that increased activity by inflammatory cytokines is beneficial to the healing process, there is ample evidence to show that a secondary or late phase of proinflammatory mediators is in fact mandatory for bone healing to proceed normally [ 3 , 40 ].…”

“…Radiographic data are presented in Table 2 . Tables 1 and 2 have in part been presented in a previous study [ 12 ]. One patient had no radiographic data after 18 months into the study as the patient chose to interrupt participation.…”

“…Nonetheless, our current understanding of the biological mechanisms regulating the pathology and recovery of Charcot arthropathy is almost entirely circumstantial in nature. In two recent studies to be discussed below, we presented evidence of the important role played by proinflammatory cytokines belonging to the Th17 subset of T helper cells [ 12 ] and by mediators of two major bone-regulating pathways [ 10 ] for bone healing in Charcot arthropathy patients. In the current study, we extended our investigation to the THh1/Th2 subset of proinflammatory cytokines.…”

MicroRNA‑139‑5p elevates skeletal myogenic differentiation of human adult dental pulp stem cells through Wnt/β‑catenin signaling pathway

“…DPSCs are located in the dental pulp, which possesses self-renewal ability and can differentiate into odontoblasts ( 4 ). Previous research has indicated that there are several factors affecting DPSC proliferation and differentiation ( 5 ). They include basic fibroblast growth factor, transforming growth factor, bone morphogenetic protein, β-phosphoglycerol and dentin ( 5 ).…”

Markers of Local Inflammation and Bone Resorption in the Acute Diabetic Charcot Foot

“…Related to this, studies have explored the possible relationship between interleukin levels and acute Charcot foot [ 17 , 27 – 29 ] and found increased levels of interleukin-1 receptor antagonist (IL-1RA), tumor necrosis factor α (TNF- α ), interleukin-6 (IL-6), and interleukin-17 subtypes A, E, and F (IL-17A/E/F), as well as decreased levels of interleukin-1 β (IL-1 β ) and interleukin-8 (IL-8).…”