Model for osteoclast resorptive activity in Charcot osteoarthropathy in M-CSF + RANKL-treated cultures before and after the addition of anti-TNF-α (a). In the presence of TNF-α, continuous multidented pits (defined as lacunae or trenches) with increased area of resorption both on the surface and under the surface are seen more frequently compared with less frequently noted unidented pits (single resorption event). Resorption is prolonged and is not interrupted by migration episodes. After the inhibition of TNF-α, the percentage of multidented pits is reduced with a corresponding increase in the percentage of unidented pits suggesting that the resorptive cycle is restored. Resorption alternates with migration and intermittent resorption events occur away from each other (unidented pits). The observed differences in the resorption before and after the addition of anti-TNF-α suggest that TNF-α (via cathepsin K upregulation) modulates the resorptive behaviour of osteoclasts generated from Charcot patients and these highly active osteoclasts are capable of extensive lacunar resorption with aberrant pit morphology and geometry due to reduced migration, increased survival, and reduced apoptosis. The proposed role of TNF-α in the pathogenesis of pathological bone destruction in the acute Charcot foot (b).