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。我们以前曾报道，苯妥英钠和环孢素，众所周知的药物引起牙龈增生，抑制组织蛋白酶-L mRNA的表达，以及其在牙龈成纤维细胞的活性。因此，我们首先研究了另一种引起这种疾病的药物硝苯地平对溶酶体酶活性的影响。结果，硝苯地平也抑制了组织蛋白酶-L mRNA的表达及其活性。因此，所有这三种药物引起牙龈过度生长原来抑制组织蛋白酶-L的活性在体外。基于这一观察结果，我们研究了组织蛋白酶-L的“功能完全丧失”的体内影响，通过使用组织蛋白酶-L缺陷小鼠。组织蛋白酶-L缺陷小鼠牙龈过度生长，而野生型小鼠没有。从组织学上看，牙龈增生的特征是上皮细胞和结缔组织增厚，结缔组织中有延长的网钉，表型与人类牙龈增生极为相似，另一方面，众所周知，环孢素具有抗血管生成作用，在药物诱导的牙龈增生病变中观察到很少新合成的毛细血管。我们发现，这是伴随着减少血管内皮生长因子的表达，通过抑制c-jun N-末端激酶的活性环孢素。最后，它是必要的，以保持特定的血药浓度牙龈过度生长。据报道，在负责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，我们认为检测基因型可能是预测疾病易感性的一个很有用的方法。

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.