Charcot Foot and the Osteoclast: More Than Just Cytokines

CATEGORY: Basic Sciences/Biologics INTRODUCTION/PURPOSE: Charcot foot is a serious complication of diabetes present in up to 13% carrying with high morbidity (dislocations, fractures, deformities) and up to 14% mortality. In Charcot, osteoclasts are found in increased numbers and with increased activity3,4 while C-telopeptide of type I collagen (CTX) is upregulated as opposed to ALP suggesting this is indeed an osteoclast and not an osteoblast disease. METHODS: The scientific literature was reviewed to identify relevant osteoclastic activators and their role in the hyper activated state. We will also show videos of our current micromanipulation research techniques used to study osteoclast inhibitors in the lab. RESULTS: The blood of Charcot patients is different at the nano level. Micro-nano-particles are extracellular vesicles derived from cells into plasma. Microparticles are found in increased quantity in Charcot;which contain more cytokines; known osteoclast activators. MicroRNAs – Epigenetic changes also are in Charcot; 16 different circulating microRNA known osteoclast activators are associated with Charcot. Advanced glycation end products (AGE). The hyperglycemic state in Charcot is a driving force in pathogenesis. AGEs are normal proteins turned dud after hyperglycemic induced glycation, a post translational modification which is irreversible affects both intracellular and extracellular proteins. AGEs may bind receptor RAGE, increasing osteoclast activity . RANKL is the main osteoclast differentiator and activator. RANKL has been the target of osteoclast control almost since it was found in 1998 . CONCLUSION: Charcot mediated bony destruction and remodeling; both of which are mediated by the osteoclast has traditionally had a tremendous cytokine focus. Our review suggests the mechanism for modifying a Charcot response on a local and systemic level. It is interesting to note that osteoclast inhibitors Denosumab, Bisphosphonates, Calcitonin and osteoblcast activators rPTH are not completely effective in switching off the Charcot response, implying there is a far more complex interaction between the inflammatory response, osteoclastic stimulators and osteoblastic inhibitors.