Drug-induced gingival overgrowth, the chronic side effect of calcium 
antagonists, is frequently seen due to the increase in patients with 
hypertension, although the etiology of the disease is largely unknown. I-cell 
disease, which accompanies gingival overgrowth, is characterized by a deficiency 
in UDP-N-acetyl-glucosamine and is classified as one of the lysosomal storage 
diseases. Here, we hypothesized that a common mechanism may underlie the 
etiology of gingival overgrowth seen in patients treated with calcium antagonist 
and in patients with I-cell disease. A calcium antagonist, nifedipine, 
specifically suppressed cathepsin-L activity and mRNA expression, but not that 
of cathepsin-B in cultured gingival fibroblasts. The activity of cathepsin-L was 
suppressed up to 50% at 24 hours after treatment of the cells with the reagent. 
The selective suppression of cathepsin-L activity appeared not to be dependent 
on Ca(2+), since treatment of the cells with thapsigargin suppressed both 
cathepsin-B and -L activity. Mice deficient in the cathepsin-L gene manifested 
enlarged gingivae. Histological observation of the gingivae demonstrated typical 
features of acanthosis, a phenotype very similar to that of experimentally 
induced gingival overgrowth. Since cathepsin-L deficiency was reported to be 
associated with thickening of the skin, impaired cathepsin-L activity may play a 
key role in the establishment of skin and gingival abnormalities seen in I-cell 
disease. In addition, reduced cathepsin-L activity may play an important role in 
inducing drug-induced gingival overgrowth.