Study on the pathogenesis of drug-induced gingival overgrowth -A study with deficient mice

药物引起的牙龈过度生长是某些药物的副作用。我们之前报道过苯托英和环孢素这两种众所周知的导致牙龈过度生长的药物可以抑制牙龈成纤维细胞中cathepsin-L mRNA的表达及其活性。因此，我们首先研究了另一种引起该病的药物硝苯地平对溶酶体酶活性的影响。硝苯地平还能抑制组织蛋白酶- l mRNA的表达和活性。因此，这三种引起牙龈过度生长的药物在体外都抑制了组织蛋白酶- l的活性。在此基础上，我们利用cathepsin-L缺陷小鼠研究了cathepsin-L“完全丧失功能”的体内效应。组织蛋白酶- l缺失小鼠出现牙龈过度生长，而野生型小鼠没有。组织学上，牙龈过度生长的特征是上皮增厚，结缔组织增厚，结缔组织中有细长的网状钉，表型与人类牙龈过度生长极为相似。另一方面，众所周知环孢素具有抗血管生成作用，在药物性牙龈过度生长的病变中很少观察到新合成的毛细血管。我们发现这伴随着血管内皮生长因子的表达减少，通过环孢素抑制c jun n末端激酶活性。最后，保持一定的血药浓度是导致牙龈过度生长的关键。据报道，在代谢这些药物的酶的编码区存在几个单核苷酸多态性。我们发现特定的基因型与代谢能力差密切相关，因此，我们得出结论，检测基因型可能在预测疾病易感性方面非常有用。

Drug-induced gingival overgrowth develops as a side effect of certain medications. We previously reported that phenytoin and cyclosporine, well known drugs causing gingival overgrowth, suppressed cathepsin-L mRNA expression as well as its activity in gingival fibroblasts. Therefore, we first investigated the effects of nifedipine, another drug causing the disease, on lysosomal enzyme activity. As a result, nifedipine also suppressed cathepsin-L mRNA expression and its activity. Thus, all three drugs causing gingival overgrowth turned out to suppress cathepsin-L activity in vitro. Based on this observation, we investigated the in vivo effects of "complete loss of function" of cathepsin-L by using cathepsin-L deficient mice. Cathepsin-L deficient mice developed gingival overgrowth, while wild type mice did not. flistologically, overgrown gingival was characterized by a thickened epithelium as well as thickened connective tissue with elongated rete pegs into the connective tissue, phenotype extremely similar to that observed in human gingival overgrowth.On the other hand, it is well known that cyclosporine exhibit anti-angiogenic effect, and that very few newly synthesized capillaries are observed in the lesion of drug-induced gingival overgrowth. We found that this was accompanied by the reduced expression of vascular endothelial growth factor via suppression of c jun N-terminal kinase activity by cyclosporine.Finally, it is essential to keep particular blood drug concentration to develop gingival overgrowth. It has been reported that there exist several single nucleotide polymorphisms in the coding region of the enzyme responsible for metabolizing these drugs We found that particular genotype is closely associated with poor metabolic ability, and thus, we concluded that examining the genotype may be quite useful in predicting the disease susceptibility.