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.

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CD59-antigen expression on the surface membranes of erythrocytes, granulocytes, monocytes, lymphocytes, and platelets was determined by flow cytometry in 34 healthy controls and 17 patients with paroxysmal nocturnal hemoglobinuria (PNH). In all PNH patients, CD59-negative erythrocytes accounted for > 10% of the total erythrocyte population. Two erythrocyte populations (CD59-negative and normally positive or CD59-negative and partly positive), three populations (CD59-negative, partly positive, and normally positive), and one population (CD59-negative) were demonstrated in ten, six, and one patients, respectively. However, CD59-negative granulocytes did not account for > 10% of the total granulocytes in two patients, and one of them had only a CD59 normally positive granulocyte population. A particular granulocyte population extended over both CD59-negative and partly positive areas was shown in two patients. Two populations (CD59-negative and normally positive) and one population (CD59-negative) were demonstrated in monocytes and lymphocytes. CD59-negative lymphocytes accounted for > 50% of the total lymphocytes in only two patients. Three patients had a CD59 normally positive lymphocyte population. Percentages of CD59-positive platelet population in normal controls were widely various. Therefore, it was usually difficult to discriminate between PNH-affected and normal platelets. Thus, the flow cytometric profiles of CD59-antigen expression varied not only between PNH patients but between cell lineages. The present results and our prior study indicate that CD59 flow cytometry using erythrocytes and granulocytes is most suitable for diagnosing PNH.