Proteoglycans and age-related deterioration of bone toughness

蛋白多糖与年龄相关的骨韧性退化

• 批准号: 10418752
• 负责人: Jean X Jiang
• 金额: $ 45.43万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418752
• 关键词: Achievement; Address; Affect; Age; Age Factors; Age-Related Bone Loss; Aging; Animal Model; Biochemical; Biological; Biomechanics; Bone Density; Bone Diseases; Bone Matrix; Bone Tissue; Cadaver; Cell model; Collagen; Collagen Fibril; Computer Models; Crystallization; Deterioration; Development; Elements; Fibrinogen; Fracture; GAG Gene; Gender; Glycosaminoglycans; Goals; Healthcare; Human; Hydration status; In Situ; In Vitro; Knockout Mice; Lead; Measures; Mechanics; Methodology; Minerals; Modeling; Mucopolysaccharidoses; Mus; Orthopedics; Osteoblasts; Osteogenesis Imperfecta; Osteopenia; Osteoporosis; Outcome Study; Pathway interactions; Patients; Pilot Projects; Play; Population; Porosity; Premature Mortality; Prevention; Protein Biochemistry; Proteins; Proteoglycan; Raman Spectrum Analysis; Rattus; Research; Research Personnel; Resolution; Risk; Role; Sampling; Techniques; Testing; Thinness; Tissue Engineering; Tissue Model; Tissues; Treatment Efficacy; Water; age related; aging population; biglycan; bone; bone cell; bone fragility; bone loss; bone quality; bone toughness; cohesion; cortical bone; crosslink; crystallinity; decorin; disability; fragility fracture; glycation; high risk; improved; in vitro Model; in vivo; insight; mortality; mouse model; nanomechanics; novel therapeutic intervention; subcutaneous; substantia spongiosa

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.

项目摘要 骨骼易碎性骨折是对我们迅速老龄化人群的医疗保健的主要关注点，因为 长期残疾甚至过早死亡。这种断裂不仅是由于骨矿物质密度的损失 （BMD），但也是由于骨骼不同层次结构的不良组成/结构变化所致。这是一个众所周知的 脱水时骨完全失去其韧性的事实。但是，基本机制仍然是 难以捉摸。我们的初步结果表明，蛋白聚糖（PGS），一组非胶原蛋白 （NCP）在骨基质中，在骨组织韧性中起关键作用。此外，我们的结果还表明PGS 在骨基质中，随着骨骼韧性的相关恶化而降低。而且，我们的飞行员 研究表明，累积的非酶糖糖化会减少PG，并且可以补偿这种减少 通过通过下给药将插科打到骨基质中，从而改善了骨骼的韧性。对此 最后，我们假设（1）PG含有吸引和保留结合水中的糖胺聚糖（插科打） 骨基质，从而调节骨基质的原位水合状态，然后施加显着 对骨骼韧性的影响。 （2）衰老可能会导致骨基质中的堵塞/PG损失，从而导致 骨骼韧性的显着恶化，而插科打的补充剂可能会阻止这种与年龄有关的 骨骼韧性的恶化。我们提出了两个具体目的以解决这些假设。目标1：确定 堵塞骨骼的堵嘴/PG的基本机制。在这里，我们将使用体外人类尸体骨骼， 体内鼠标和计算模型以三个子启示测试假设：（1）确定堵嘴的作用 在使用体外模型中保留骨基质中的结合水。 （2）确定插科打/pg在 使用KO小鼠模型在体内固定骨骼。 （3）验证插科打在韧性中的机理作用 使用计算方法。 AIM 2：确定与年龄相关的GAG/PG的损失及其对 与年龄有关的骨骼韧性恶化。在这里，我们将使用体内人体尸体骨和体内动物 在三个子aims中检验假设的模型：（1）确定堵嘴/PG的年龄相关效果 使用人尸体样品的两种性别的皮质和小梁骨。 （2）确定效果 骨细胞使用小鼠骨离体模型和 成骨细胞模型。 （3）确定补充堵嘴在威胁年龄相关的堵嘴损失中的疗效 并使用老化的大鼠模型保持骨骼的韧性。完成此目标后，我们希望 了解插科打s/pg在骨骼韧性的年龄和与性别相关的恶化中的机械作用，一个 与年龄相关的插科打损失的潜在途径，以及补充插科打s的功效 骨骼韧性的丧失。这项研究的结果将为年龄相关的骨骼脆弱性提供重要的见解 裂缝并促进建立新的策略，以预测和预防老年人的脆弱性裂缝 人口。