Charcot Neuroarthropathy may be the RAGE

Abstract

Charcot neuroarthropathy (CNA) is a degenerative bone disease of unknown origin that occurs in the ankle and midfoot. While not exclusive to patients with diabetes, CNA will develop in about 0.1-2.5% of those with diabetes [1,2]. Recent work has focused on understanding the common link between inflammation induced by oxidative stress and the ensuing accumulation of advanced glycation end products (AGEs) leading to impaired bone mineral matrix mineralization and reduced bone strength in CNA. Collagen cross-linking is important for bone strength but non-enzymatic crosslinking results in an accumulation of AGEs in bone, accelerated by oxidative stress. AGEs stimulate apoptosis of osteoblastic cells mediated through RAGE, the pattern recognition receptor for AGE. AGE-RAGE interactions alter intracellular signaling via pro-inflammatory cytokines that further propagate diabetic complications. sRAGE is a soluble form of RAGE that competes with membrane-bound RAGE receptors for AGEs and functions as a decoy to “mop up” circulating AGEs, preventing them from binding to RAGE and causing an inflammatory cascade. A reduction in serum sRAGE is associated with increased vascular risk factors in diabetes mellitus and the metabolic syndrome. Recently, it was shown that bone specimens removed from CNA patients display reduced trabecular number and the presence of woven bone. We have previously shown derangements in collagen structure of the Achilles tendon and reduced calcaneal bone stiffness in CNA patients correlated with a marked reduction in circulating sRAGE. These results suggest a relationship between impaired AGE defense, bone turnover, and reduced bone quality in CNA. Based on limited studies relating RAGE to bone status and a few animal studies using sRAGE administration to interfere with RAGE expression, we speculate that sRAGE administration may have potential to interrupt osteoclastic activation in those who lack adequate endogenous production such as patients with CNA.