Collagen advanced glycation inhibits its Discoidin Domain Receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts.
Collagen advanced glycation inhibits its Discoidin Domain Receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts.
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DOI：
10.1016/j.bone.2013.10.001
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发表时间：
2014-01
期刊：
影响因子：
4.1
通讯作者：
Trackman, Philip C.
中科院分区：
文献类型：
--
作者：
Khosravi, Roozbeh;Sodek, Katharine L.;Faibish, Michael;Trackman, Philip C.
糖尿病会增加骨折的风险。有机和无机骨细胞外基质成分决定骨强度。先前的研究表明，在糖尿病中，胶原蛋白的糖化导致胶原蛋白分子的异常排列和脆弱的骨骼。糖尿病性骨脆性还归因于赖氨酰氧化酶依赖性胶原交联水平降低。糖尿病骨中存在较低酶促胶原交联的潜在机制尚未直接研究。在这里，我们确定在原代成骨细胞培养的赖氨酰氧化酶蛋白的调节I型胶原和胶原修饰的羧甲基化（CML-胶原），一种形式的晚期糖基化终产物。数据表明，非糖化胶原上调赖氨酰氧化酶水平在初级未分化和分化小鼠和大鼠成骨细胞培养，而CML-胶原不能调节赖氨酰氧化酶在这些细胞。在DDR2 shRNA敲除研究中确定，胶原蛋白与盘状结构域受体-2（DDR2）的结合介导赖氨酰氧化酶增加。DDR2的结合和激活被胶原蛋白糖化破坏，指出了糖尿病骨中赖氨酰氧化酶水平降低和随后的低赖氨酰氧化酶衍生交联的机制。我们的研究表明，胶原整合素的相互作用可能不会发挥重要作用，上调赖氨酰氧化酶。此外，晚期糖基化终产物受体的非胶原配体未能改变赖氨酰氧化酶水平。结合已发表的研究，出现了一种新的理解，其中正常胶原刺激的DDR2和整合素信号传导的糖尿病和年龄依赖性抑制，以及独立的晚期糖基化刺激的RAGE信号传导，各自导致糖尿病骨质减少的不同方面。
Diabetes increases the risk of bone fracture. Organic and inorganic bone extracellular matrix components determine bone strength. Previous studies indicate that in diabetes, glycation of collagen causes abnormal arrangements of collagen molecules and fragile bones. Diabetic bone fragility is additionally attributed to reduced levels of lysyl oxidase enzyme-dependent collagen cross-links. The mechanism underlying the presence of lower enzymatic collagen cross-links in diabetic bone has not been directly investigated. Here we determine in primary osteoblast cultures the regulation of lysyl oxidase protein by type I collagen and collagen modified by carboxymethylation (CML-collagen), a form of advanced glycation endproducts. Data indicate that non-glycated collagen up-regulates lysyl oxidase levels both in primary non-differentiated and in differentiating mouse and rat osteoblast cultures, while CML-collagen fails to regulate lysyl oxidase in these cells. Collagen binding to Discoidin Domain Receptor-2 (DDR2) mediates lysyl oxidase increases, determined in DDR2 shRNA knockdown studies. DDR2 binding and activation were disrupted by collagen glycation, pointing to a mechanism for the diminished levels of lysyl oxidase and consequent low lysyl oxidase-derived cross-links in diabetic bone. Our studies indicate that collagen-integrin interactions may not play a major role in up-regulating lysyl oxidase. Furthermore, non-collagenous ligands for the receptor for advanced glycation end products (RAGE) failed to alter lysyl oxidase levels. Taken together with published studies a new understanding emerges in which diabetes- and age-dependent inhibition of normal collagen-stimulated DDR2- and integrin-signaling, and independent advanced glycation-stimulated RAGE-signaling, each contributes to different aspects of diabetic osteopenia.
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