Laboratory Investigations Hypoxia Induces Giant Osteoclast Formation and Extensive Bone Resorption in the Cat

Dental disease due to osteoclast (OC) overac- tivity reaches epidemic proportions in older domestic cats and has also been reported in wild cats. Feline odonto- clastic resorptive lesions (FORL) involve extensive resorption of the tooth, leaving it liable to root fracture and subsequent loss. The etiopathogenesis of FORL re- mains unclear. Here, we explore the hypothesis that FORL is associated with hypoxia in the oral microenvi- ronment, leading to increased OC activity. To investigate this, we developed a method of generating OCs from cat blood. Reducing O2 from 20% to 2% increased the mean area of OC eightfold from 0.01 to 0.08 mm 2 . In hypoxic cultures, very large OCs containing several hundred nu- clei were evident (reaching a maximum size of 14 mm 2 ). Cultures exposed to 2% O2 exhibited an increase of 13- fold in the area of bone slices covered by resorption lacunae. In line with this finding, there was a significant increase in cells differentiating under hypoxic conditions, reflected in increased expression of cathepsin K and proton pump enzymes. In conclusion, these results dem- onstrate that oxygen tension is a major regulator of OC formation in the cat. However, in this species, hypoxia induces the formation of ''giant'' OCs, which can be so large as to be visible with the naked eye and yet also ac- tively resorb. This suggests that local hypoxia is likely to play a key role in the pathogenesis of FORL and other inflammatory conditions that are associated with bone resorption in cats.