Molecular Pathological Aspects of Spontaneous Mouse Hereditary Keratoconus

在埼玉癌症中心发现了两种自发性遗传性圆锥角膜样角膜病变小鼠，分别命名为SKC （spontaneous keratoconus）和JKC （Japanese keratoconus）小鼠。SKC小鼠在实验室小鼠封闭群体中发现，JKC小鼠在日本野鼠（小家鼠）中发现。在这项研究中，我们对这些小鼠及其角膜的分子病理学和遗传学方面进行了特别的研究。SKC和JKC小鼠的角膜病变均以常染色体隐性遗传方式遗传，SKC小鼠和JKC小鼠的连锁分析将每个负责或易感基因分别链接到小鼠的第17和13号染色体上。JKC小鼠的角膜病变在两性中都有发生，而SKC小鼠的角膜病变选择性地发生在雄性中（SKC雌性小鼠的角膜病变仅在极罕见的情况下发生）。然而，有趣的是，在雌性SKC小鼠中，当在大约4周龄时给予雄激素时，角膜病变在许多情况下（66%）出现。这表明SKC小鼠的角膜病变是雄激素依赖性的（需要雄激素发生）。为了揭示雄激素依赖性的机制，我们检测了小鼠角膜中雄激素的表达。免疫组化法检测不同类型角膜细胞细胞核中雄激素受体的表达，RT-PCR法检测小鼠角膜中雄激素受体在RNA水平的表达。这表明雄激素直接作用于角膜细胞导致角膜病变。此外，我们发现小鼠角膜中不仅有雄激素受体，还有a型和b型雌激素受体的表达。进一步的研究表明，性类固醇受体也在人类角膜中表达。性类固醇可能在SKC小鼠、其他小鼠甚至人类的圆锥角膜和其他角膜病变的发展中发挥重要作用。

Two lines of mouse with spontaneous hereditary keratoconus-like keratopathy were discovered in Saitama Cancer Center, which were named SKC (spontaneous keratoconus) and JKC (Japanese Keratoconus) mouse. SKC mouse was found in a closed colony of laboratory mouse, while JKC mouse was found in Japanese wild mice (Mus musculus molossinus). In this study, we characterized these mice and their corneas with special interests in their molecular-pathological and genetic aspects. Keratopathy of both SKC and JKC mice was inherited in an autosomal recessive manner, and linkage analyses in SKC mouse and JKC mouse linked each responsible or susceptible gene, to respectively, mouse chromosome 17 and 13.While keratopathy of JKC mice occurred in both genders that of SKC mice occurred selectively in males (keratopathy occurred only in extremely rare cases in female SKC mice). Interestingly, however, in female SKC mice the keratopathy appeared in many cases (66%) when androgen was given to them at approximately 4 weeks of age. These suggest that keratopathy of SKC mice is androgen-dependent (requires androgen to occur). In an effort to reveal the mechanism of this androgen-dependency, we examined the expression of androgen in mouse corneas. Expression of androgen receptors was detected in nuclei of various types of corneal cells as judged by immunohistochemistry, and expression of this receptor at RNA level was also detected by RT-PCR in mouse corneas. These suggest that androgen directly acts in corneal cells to cause keratopathy. In addition, we found that not only androgen receptor but also estrogen receptors of both a and b type are expressed in mouse corneas. further study revealed that sex steroid receptors are expressed in human corneas as well. Sex steroids may play an important role in development of keratoconus and other keratopthy in SKC mice and perhaps other mice or even in humans.