title: Cathepsin-L, a key molecule in the pathogenesis of drug-induced and I-cell disease-mediated gingival overgrowth: a study with cathepsin-L-deficient mice.
abstract: 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.
authors.affiliation: Department of Pathophysiology/Periodontal Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8525, Japan. fusanori@md.okayama-u.ac.jp
authors.forename: Fusanori
authors.initials: F
authors.lastname: Nishimura
authors.forename: Hisa
authors.initials: H
authors.lastname: Naruishi
authors.forename: Koji
authors.initials: K
authors.lastname: Naruishi
authors.forename: Teruo
authors.initials: T
authors.lastname: Yamada
authors.forename: Junzo
authors.initials: J
authors.lastname: Sasaki
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murayama
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005881:Gingiva / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009081:Mucolipidoses / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D009543:Nifedipine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D019284:Thapsigargin; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D009543:Nifedipine; D002118:Calcium