Proteoglycans and age-related deterioration of bone toughness

项目摘要 骨脆性骨折是我们快速老龄化人口的主要医疗保健问题，因为骨脆性骨折的风险很高。 长期残疾甚至过早死亡。这种骨折不仅是由于骨矿物质密度的损失 (BMD)，但也由于在不同层次的骨的不利组成/结构变化。这是一个众所周知的 事实上，骨骼在脱水时会完全失去韧性。然而，潜在的机制仍然是 难以捉摸。我们的初步结果表明，蛋白聚糖（PGs），一个亚组的非胶原蛋白， 骨基质中的NCPs在骨组织韧性中起着关键作用。此外，我们的研究结果还表明， 随着年龄的增长，骨基质中的钙离子减少，骨韧性随之下降。此外，我们的飞行员 研究表明，累积的非酶糖化降低PG，这种降低可以得到补偿 通过皮下给药将GAG递送至骨基质，从而改善骨的韧性。本 最后，我们假设（1）PG含有糖胺聚糖（GAG），可以吸引和保留结合水， 骨基质，从而调节骨基质的原位水合状态，随后施加显著的 影响骨骼的韧性。(2)衰老可能导致骨基质中GAG/PG的丢失，从而导致 骨韧性的显著恶化，而补充GAG可以阻止这种年龄相关的 骨韧性下降。我们提出了两个具体的目标来解决这些假设。目标1：确定 GAGs/PGs在骨增韧中的潜在机制。在这里，我们将使用体外人类尸体骨， 在体内小鼠，和计算模型，以测试在三个子目标的假设：（1）确定糖胺聚糖的作用 在保留结合水在骨基质中使用的体外模型。(2)确定性别平等咨询小组/方案指导小组在以下方面的作用： 使用KO小鼠模型在体内增韧骨。(3)验证GAG在增韧骨中的机制作用 使用计算方法。目标2：确定糖皮质激素/前列腺素与年龄相关的损失及其对 与年龄相关的骨韧性退化。在这里，我们将使用离体人尸体骨和体内动物 模型来检验三个子目标的假设：（1）确定年龄相关的GAGs/PGs对韧性的影响 使用人尸体骨样本对两种性别的皮质骨和松质骨进行了测量。(2)确定影响 使用小鼠骨离体模型测定非酶糖化对骨细胞合成PG的影响， 成骨细胞模型。(3)确定补充GAG在阻止年龄相关GAG丢失方面的有效性 和维持骨骼韧性的作用。在完成这个目标后，我们预期 了解GAG/PG在与年龄和性别相关的骨韧性恶化中的机制作用， 与年龄相关的GAG损失的潜在途径，以及补充GAG在阻止与年龄相关的 骨韧性丧失。这项研究的结果将为年龄相关的骨脆性提供重要的见解 并促进预测和预防老年人脆性骨折的新策略的发展 人口

PROJECT SUMMARY Bone fragility fractures are a major concern of health care of our rapidly aging populations due to the high risk of long-term disability and even premature mortality. Such fractures are not only due to loss of bone mineral density (BMD), but also due to adverse composition/structural changes at different hierarchies of bone. It is a well-known fact that bone loses its toughness completely when dehydrated. However, the underlying mechanism is still elusive. Our preliminary results suggest that proteoglycans (PGs), a sub group of non-collagenous proteins (NCPs) in bone matrix, play a pivotal role in bone tissue toughness. In addition, our results also reveal that PGs in bone matrix decreases with aging with the associated deterioration of bone toughness. Moreover, our pilot study shows that accumulated non-enzymatic glycation decreases PGs and this decrease can be compensated by delivering GAGs to bone matrix by subdermal administration, thus improving the toughness of bone. To this end, we hypothesize that (1) PGs contain glycosaminoglycans (GAGs) that attract and retain bound water in bone matrix, thus regulating the in situ hydration status of bone matrix and subsequently imposing a significant effect on the toughness of bone. (2) Aging may cause loss of GAGs/PGs in bone matrix, thus leading to significant deterioration of bone toughness, whereas supplement of GAGs may deter such age-related deterioration of bone toughness. We proposed two specific aims to address the hypotheses. Aim 1: Determine the underlying mechanism of GAGs/PGs in toughening of bone. Here, we will use in vitro human cadaveric bone, in vivo mouse, and computational models to test the hypothesis in three subaims: (1) Determine the role of GAGs in retaining bound water in bone matrix using an in vitro model. (2) Determine the role of GAGs/PGs in toughening of bone in vivo using KO mouse models. (3) Verify the mechanistic role of GAGs in toughening bone using a computational approach. Aim 2: Determine the age-related loss in GAGs/PGs and its contribution to the age-related deterioration of bone toughness. Here, we will use ex vivo human cadaver bone and in vivo animal models to test the hypothesis in three subaims: (1) Determine age-related effect of GAGs/PGs on the toughness of cortical and trabecular bone for both genders using human cadaveric bone samples. (2) Determine the effect of nonenzymatic glycation on the synthesis of PGs by bone cells using a mouse bone ex vivo model and osteoblast cell models. (3) Determine the efficacy of supplemental GAGs in deterring age-related loss of GAGs and maintaining the toughness of bone using an aging rat model. Upon completion of this aim, we expect to understand the mechanistic role of GAGs/PGs in the age and gender-related deterioration of bone toughness, a potential pathway of age-related loss of GAGs, and the efficacy of supplementing GAGs in deterring age-related loss of bone toughness. The outcomes of this study will provide important insights to age-related bone fragility fractures and facilitate development of new strategies in prediction and prevention of fragility fractures in aged population.