Yamagishi S, Nakamura K, Matsui T, Takeuchi Masayoshi
Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Med Hypotheses. 2006;66(2):273-5. doi: 10.1016/j.mehy.2005.08.042. Epub 2005 Oct 10.
In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs-their receptor (RAGE) interactions are involved in the development and progression of diabetic retinopathy. Bisphosphonates are potent inhibitors of bone resorption and are widely used drugs for the treatment of osteoporosis and osteolytic bone metastasis. Recently, farnesyl pyrophosphate synthase has been shown as a molecular target of nitrogen-containing bisphosphonates, and inhibition of post-translational prenylation of small molecular weight G proteins is likely involved in their anti-resorptive activity on osteoclasts. NADPH oxidase-derived reactive oxygen species (ROS) generation is required for the AGE-RAGE signaling in vascular wall cells, and small G protein Rac is a critical component of vascular NADPH oxidase complex. These observations let us to speculate that minodronate, a newly developed nitrogen-containing bisphosphonate, might be a promising remedy for treating patients with diabetic retinopathy by inhibiting the AGE-RAGE signaling pathways through suppression of ROS generation via inhibition of Rac prenylation. In this paper, we like to propose the possible ways of testing our hypotheses: (1) Does treatment with minodronate decrease the risk for the development and progression of diabetic retinopathy in osteoporotic patients? (2) If the answer is yes, is this beneficial effect of minodronate superior to that of other nitrogen-noncontaining bisphosphonates with equihypolipidemic properties? (3) Does minodronate treatment suppress NADPH oxidase-mediated ROS generation in retinas of diabetic animals? (4) Does treatment with pyridoxamine, a post-Amadori inhibitor of AGE formation, attenuate these beneficial effects of minodronate on diabetic retinopathy? These clinical and animal studies could clarify whether the use of minodronate is of benefit in patients with AGE-RAGE-related disorders such as diabetic retinopathy, even in the absence of osteoporosis.
在糖尿病中，晚期糖基化终末产物（AGEs）的形成和积累不断进展。越来越多的证据表明，AGEs与其受体（RAGE）的相互作用参与了糖尿病视网膜病变的发生和发展。双膦酸盐是强效的骨吸收抑制剂，是治疗骨质疏松症和溶骨性骨转移的常用药物。最近，法尼基焦磷酸合酶已被证明是含氮双膦酸盐的分子靶点，抑制小分子量G蛋白的翻译后异戊二烯化可能与其对破骨细胞的抗吸收活性有关。血管壁细胞中AGE-RAGE信号传导需要NADPH氧化酶衍生的活性氧（ROS）生成，小G蛋白Rac是血管NADPH氧化酶复合物的关键成分。这些观察结果使我们推测，新开发的含氮双膦酸盐米诺膦酸可能是一种有前途的治疗糖尿病视网膜病变患者的药物，它通过抑制Rac异戊二烯化来抑制ROS生成，从而抑制AGE-RAGE信号通路。在本文中，我们想提出检验我们假设的可能方法：（1）米诺膦酸治疗是否能降低骨质疏松症患者发生和发展糖尿病视网膜病变的风险？（2）如果答案是肯定的，米诺膦酸的这种有益作用是否优于其他具有同等降血脂特性的不含氮双膦酸盐？（3）米诺膦酸治疗是否能抑制糖尿病动物视网膜中NADPH氧化酶介导的ROS生成？（4）吡哆胺（一种AGE形成的阿马多里产物后抑制剂）治疗是否会减弱米诺膦酸对糖尿病视网膜病变的这些有益作用？这些临床和动物研究可以阐明，即使在没有骨质疏松症的情况下，使用米诺膦酸对患有AGE-RAGE相关疾病（如糖尿病视网膜病变）的患者是否有益。
