Miyata T, Notoya K, Yoshida K, Horie K, Maeda K, Kurokawa K, Taketomi S
Institute of Medical Sciences, Tokai University School of Medicine, Isehara, Japan.
J Am Soc Nephrol. 1997 Feb;8(2):260-70. doi: 10.1681/ASN.V82260.
Advanced glycation end products (AGE) are formed in long-lived matrix proteins by a nonenzymatic reaction with sugar. The presence of AGE in beta 2-microglobulin-amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits, was recently demonstrated. This suggested a potential link of AGE in bone resorption and initiated this investigation of whether AGE enhance bone resorption. When mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, both AGE-modified beta 2-microglobulin and BSA increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts of those modified with the early glycation products did not. AGE proteins, however, did not increase the number of newly formed osteoclasts, even in the coculture of mouse bone marrow cells with osteoblastic cells isolated from mouse calvaria. Enhanced bone resorption was also observed when unfractionated bone cells were cultured on AGE-modified dentin slices. AGE-enhanced bone resorption was effectively inhibited by calcitonin and ipriflavone, both of which are inhibitors of bone resorption. AGE-enhanced bone resorption was further supported by in vivo evidence that rat bone particles-upon incubation with glucose for 60 days (AGE-bone particles)-when implanted subcutaneously in rats, were resorbed to a much greater extent than control bone particles upon parallel incubation without glucose. These findings suggest that AGE enhance osteoclast-induced bone resorption. Although the mechanism remains unknown, AGE are unlikely to promote differentiation of osteoclast progenitors into osteoclasts, suggesting that AGE activate osteoclasts or alter microenvironments favorable for bone resorption by osteoclasts. The modification of bone matrices with AGE might play a role in the remodeling of senescent bone matrix tissues, further implicating a pathological significance of AGE in dialysis-related amyloidosis or osteoporosis associated with diabetes and aging.
晚期糖基化终产物（AGE）是由糖与长寿基质蛋白发生非酶促反应形成的。最近有研究表明，在透析相关性淀粉样变性的β2-微球蛋白淀粉样纤维中存在AGE，其特征之一是淀粉样沉积物周围的骨吸收加速。这提示了AGE与骨吸收之间可能存在联系，并引发了关于AGE是否会增强骨吸收的研究。当将含有破骨细胞的小鼠未分级骨细胞培养在牙本质切片上时，AGE修饰的β2-微球蛋白和牛血清白蛋白（BSA）均增加了破骨细胞形成的吸收陷窝数量，而用早期糖基化产物修饰的正常对应物则没有。然而，即使在小鼠骨髓细胞与从小鼠颅骨分离的成骨细胞共培养时，AGE蛋白也不会增加新形成的破骨细胞数量。当未分级的骨细胞在AGE修饰的牙本质切片上培养时，也观察到了骨吸收增强。降钙素和依普黄酮均能有效抑制AGE增强的骨吸收，它们都是骨吸收抑制剂。体内证据进一步支持了AGE增强骨吸收的观点，即大鼠骨颗粒在与葡萄糖孵育6０天（AGE骨颗粒）后，皮下植入大鼠体内时，其吸收程度比平行孵育无葡萄糖的对照骨颗粒要大得多。这些发现表明AGE增强了破骨细胞诱导的骨吸收。尽管其机制尚不清楚，但AGE不太可能促进破骨细胞祖细胞分化为破骨细胞，这表明AGE激活了破骨细胞或改变了有利于破骨细胞进行骨吸收的微环境。用AGE修饰骨基质可能在衰老骨基质组织的重塑中起作用，这进一步暗示了AGE在透析相关性淀粉样变性或与糖尿病和衰老相关的骨质疏松症中的病理意义。
