Miyata T, Kawai R, Taketomi S, Sprague S M
Department of Internal Medicine, Branch Hospital, Nagoya University School of Medicine, Japan.
Nephrol Dial Transplant. 1996;11 Suppl 5:54-7. doi: 10.1093/ndt/11.supp5.54.
Advanced glycation end-products (AGEs) are formed in long-lived matrix proteins by a non-enzymatic reaction with sugar. We recently demonstrated the presence of AGEs in amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits. This suggested a potential link of AGEs in bone resorption and led us to investigate whether AGEs enhance bone resorption. An immunohistochemical study using anti-AGE antibody revealed positive immunostaining for AGEs in bone tissues from elderly subjects. AGE-modified proteins were shown to stimulate monocyte/macrophage to secrete bone-resorbing cytokines such as interleukin-1 beta, interleukin-6 and tumour necrosis factor- alpha. AGE-modified proteins enhanced net calcium efflux in cultured neonatal mouse calvariae to a much greater extent than unmodified proteins. Furthermore, when mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, AGE-modified proteins increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts or those modified with the early glycation products did not. These findings suggest that AGEs enhance bone resorption by osteoclasts. The modification of bone matrices with AGEs might, therefore, play a pathophysiological role not only in the remodelling of senescent bone matrix tissues, but also in dialysis-related amyloidosis or osteoporosis associated with diabetes and ageing.
晚期糖基化终产物（AGEs）是通过糖与长寿基质蛋白的非酶促反应形成的。我们最近在透析相关性淀粉样变的淀粉样纤维中证实了AGEs的存在，其特征之一是淀粉样沉积物周围的骨吸收加速。这表明AGEs与骨吸收之间可能存在联系，促使我们研究AGEs是否会增强骨吸收。一项使用抗AGE抗体的免疫组织化学研究显示，老年受试者骨组织中AGEs呈阳性免疫染色。结果表明，AGE修饰的蛋白质可刺激单核细胞/巨噬细胞分泌骨吸收细胞因子，如白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α。AGE修饰的蛋白质比未修饰的蛋白质更能增强培养的新生小鼠颅骨中的净钙外流。此外，当将含有破骨细胞的小鼠全骨髓细胞培养在牙本质切片上时，AGE修饰的蛋白质增加了破骨细胞形成的吸收陷窝数量，而正常蛋白质或早期糖基化产物修饰的蛋白质则没有。这些发现表明，AGEs可增强破骨细胞的骨吸收。因此，骨基质被AGEs修饰可能不仅在衰老骨基质组织的重塑中起病理生理作用，而且在与糖尿病和衰老相关的透析相关性淀粉样变或骨质疏松症中也起作用。
