Nishimura Fusanori, Naruishi Hisa, Naruishi Koji, Yamada Teruo, Sasaki Junzo, Peters Christoph, Uchiyama Yasuo, Murayama Yoji
Department of Pathophysiology/Periodontal Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8525, Japan.
Am J Pathol. 2002 Dec;161(6):2047-52. doi: 10.1016/S0002-9440(10)64483-5.
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.
药物性牙龈增生是钙拮抗剂的慢性副作用，由于高血压患者数量增加，这种情况很常见，尽管该病的病因在很大程度上尚不清楚。伴有牙龈增生的I细胞病的特征是UDP-N-乙酰葡糖胺缺乏，属于溶酶体贮积病之一。在此，我们假设一种共同机制可能是钙拮抗剂治疗患者和I细胞病患者牙龈增生病因的基础。钙拮抗剂硝苯地平在培养的牙龈成纤维细胞中特异性抑制组织蛋白酶L的活性和mRNA表达，但不抑制组织蛋白酶B的活性。用该试剂处理细胞24小时后，组织蛋白酶L的活性被抑制高达50%。组织蛋白酶L活性的选择性抑制似乎不依赖于Ca(2+)，因为用毒胡萝卜素处理细胞会抑制组织蛋白酶B和L的活性。组织蛋白酶L基因缺陷的小鼠表现出牙龈肿大。牙龈的组织学观察显示出棘皮症的典型特征，这一表型与实验诱导的牙龈增生非常相似。由于据报道组织蛋白酶L缺乏与皮肤增厚有关，组织蛋白酶L活性受损可能在I细胞病中所见的皮肤和牙龈异常的形成中起关键作用。此外，组织蛋白酶L活性降低可能在诱导药物性牙龈增生中起重要作用。
