Charcot Pathogenesis: A Study of In Vivo Gene Expression.

Charcot neuroarthropathy is a rare but often difficult to manage disease in the neuropathic patient. Early signs such as unremarkable edema, marginal trauma, or minor infection can activate a cascade of bony destruction and lead to gross prominence or deformity, with dire consequences. The exact molecular mechanism is poorly understood. Current theory states that an inflammatory reaction leads to the activation of osteoclasts mediated by specific cytokines. Our study sought to test the genetic expression of certain biomarkers in diabetic patients with and without Charcot neuroarthropathy compared with patients with and without diabetes or neuropathy. A total of 30 patients participated in the study, 17 (57%) males and 13 (43%) females. Peripheral blood samples were drawn, and gene expression was measured using real-time polymerase chain reaction. The expression levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin showed no significant increase in the Charcot neuroarthropathy group compared with the healthy control group. We determined that the levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin were not significantly increased in Charcot neuroarthropathy patients compared with healthy control patients. These results demonstrate a need for further investigation into alternative molecular pathways to determine the exact mechanism of the disease process.

Association of Anatomical Location of Neuroarthropathic (Charcot's) Destruction with Age-and Sex-Matched Bone Mineral Density Reduction.

BACKGROUND: It is well documented that diabetes has a systemic impact on bone mineral density. Recent literature has evaluated the relationship between the development of Charcot neuroarthropathy and reduced local bone mineral density; however, it is not clear if there is an association between osteoporosis/osteopenia and Charcot onset, or, even further, location of neuroarthropathic breakdown. METHODS: We retrospectively identified and assessed 39 patients with 41 feet (4 bilateral) with a history of Charcot breakdown who underwent a bone mineral density scan over a 15-year period. Demographic, radiographic, and bone mineral density information was analyzed. RESULTS: The average patient age at the time of bone mineral density scan was 53.44 ± 8.09 years, and 52.77 ± 8.19 years at the time of Charcot diagnosis. Four feet were considered Sanders-Frykberg I (9.3%), 17 were Sanders-Frykberg II (39.5%), ten were Sanders-Frykberg III (23.3%), and 12 were Sanders-Frkyberg IV/V (27.9%). Neuroarthropathic breakdown of the rearfoot region (Sanders-Frykberg IV/V) was found to be associated and preceded by osteoporosis and osteopenia at the hip as demonstrated by a lower Z-score (P = 0.05). Charcot neuroarthropathy was not associated with poor bone health or loss of bone mineral density at the femoral neck, forearm, or lumbar spine. CONCLUSIONS: We believe that the present findings suggest a possible relationship between osteoporosis/osteopenia and the location of CN development. With these findings in mind, we conclude that patients with diabetic skeletal fragility may benefit from treatment of underlying poor bone mineral density to prevent the onset of Charcot neuroarthropathy.

Evidence of Autoimmune Involvement in the Pathogenesis of Charcot Neuroarthropathy: A Novel Hypothesis with Preliminary Data.

Charcot neuroarthropathy is a devastating condition that places patients at risk for poor outcomes. Although the condition was first described in 1703, knowledge of the causative agent(s) has yet to be fully understood. Recent advances in genetic research have helped to identify potential mechanisms and pathways for the enigmatic destruction and deformities that are often associated with the condition; however, alternative pathways have been proposed. For the purpose of this discussion, we will discuss the human leukocyte antigen, which is one of the most researched contributors to autoimmune pathology and, more recently, has been linked to diabetic complications.