Proteoglycans and age-related deterioration of bone toughness

项目总结 骨脆性骨折是我们快速老龄化人口的医疗保健的一个主要问题，因为 长期残疾，甚至过早死亡。这样的骨折不仅仅是由于骨质密度的丧失。 (BMD)，但也是由于不同骨骼层次的不利成分/结构变化所致。它是一家著名的 骨骼在脱水时完全失去韧性的事实。然而，潜在的机制仍然是 难以捉摸。我们的初步结果表明，蛋白多糖(PGs)是非胶原蛋白的一个亚群 骨基质(NCPs)在骨组织韧性中起着举足轻重的作用。此外，我们的结果还显示，PGs 在骨基质中随着年龄的增长而减少，伴随着骨韧性的恶化。另外，我们的飞行员 研究表明，累积的非酶糖化作用会降低PG，这种下降是可以补偿的 通过皮下给药将GAG输送到骨基质中，从而提高骨骼的韧性。对这件事 最后，我们假设(1)PG含有糖胺聚糖(GAG)，它能吸引和保持结合水 骨基质，从而调节骨基质的原位水化状态，并随后施加显著的 对骨骼韧性的影响。(2)衰老可能导致骨基质中GAG/PG的丢失，从而导致 骨骼韧性显著恶化，而补充GAG可能会阻止这种与年龄相关的 骨骼韧性下降。我们提出了两个具体目标来解决这些假设。目标1：确定 GAG/PGs增韧骨骼的基本机制。在这里，我们将使用体外培养的人类身体骨， 在活体小鼠身上，用计算模型来检验假设有三个子目标：(1)确定GAG的作用 使用体外模型在骨基质中保留结合水。(2)确定GAG/PG在 利用KO小鼠模型进行活体骨骼增韧。(3)验证GAG增韧骨骼的机制作用 使用计算方法。目标2：确定GAG/PG中与年龄相关的损失及其对 与年龄相关的骨骼韧性恶化。在这里，我们将使用体外人尸骨和体内动物 在三个子目标中检验假设的模型：(1)确定GAG/PGs对韧性的年龄相关效应 使用人类身体骨样本，对男女皮质骨和松质骨进行比较。(二)确定效果 用小鼠骨骼体外模型研究非酶糖基化对骨细胞合成前列腺素的影响 成骨细胞模型。(3)确定补充GAG对阻止与年龄相关的GAG丢失的效果 并使用衰老的大鼠模型来维持骨骼的韧性。在完成这一目标后，我们预计 了解GAG/PGs在年龄和性别相关的骨骼韧性恶化中的机制作用，a GAG年龄相关性丢失的可能途径及补充GAG对阻止年龄相关性GAG的作用 骨骼韧性丧失。这项研究的结果将为年龄相关的骨脆性提供重要的见解 预测和预防老年人脆性骨折的新策略 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.