Proteoglycans and age-related deterioration of bone toughness

蛋白多糖与年龄相关的骨韧性退化

基本信息

批准号：
10644016
负责人：
Jean X Jiang
金额：
$ 45.1万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644016
关键词：
Achievement Address Affect Age Age Factors Age-Related Bone Loss Aging Animal Model Binding Biochemical Biological Biomechanics Bone Density Bone Diseases Bone Matrix Bone Tissue Cadaver Cell model Collagen Collagen Fibril Compensation Computer Models Dehydration Deterioration Development Elements Fracture Gender Glycosaminoglycans Goals Healthcare Human Hydration status In Situ In Vitro Knockout Mice Measures Mechanics Methodology Minerals Modeling Mucopolysaccharidoses Mus Orthopedics Osmosis 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 cortical bone crosslink crystallinity decorin disability efficacy evaluation fragility fracture glycation high risk improved in vitro Model in vivo insight mineralization mortality mouse model nanomechanics novel therapeutic intervention risk prediction structural determinants subcutaneous substantia spongiosa

项目摘要

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.

项目概要由于骨脆性骨折的高风险，骨脆性骨折是我们快速老龄化人口医疗保健的一个主要问题。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丧失（BMD），但也是由于不同骨层次的不良成分/结构变化。这是一个众所周知的事实上，骨骼脱水时会完全失去韧性。但其根本机制仍然是难以捉摸。我们的初步结果表明，蛋白多糖（PG）是非胶原蛋白的一个亚类（NCPs）存在于骨基质中，对骨组织韧性起着关键作用。此外，我们的结果还表明 PG 骨基质随着年龄的增长而减少，并伴随着骨韧性的恶化。此外，我们的飞行员研究表明，积累的非酶糖化会减少 PG，并且这种减少可以得到补偿通过皮下注射将GAGs递送至骨基质，从而提高骨的韧性。对此最后，我们假设 (1) PG 含有糖胺聚糖 (GAG)，可以吸引并保留结合水骨基质，从而调节骨基质的原位水化状态，从而对骨基质产生显着的影响。对骨骼韧性的影响。 (2)衰老可能导致骨基质中GAGs/PGs的丢失，从而导致骨骼韧性显着恶化，而补充 GAG 可能会阻止这种与年龄相关的情况骨骼韧性恶化。我们提出了两个具体目标来解决这些假设。目标 1：确定 GAGs/PGs 强骨的基本机制。在这里，我们将使用体外人体尸体骨，体内小鼠和计算模型来检验三个子目标的假设：（1）确定 GAG 的作用使用体外模型将结合水保留在骨基质中。 (2) 确定GAG/PG的作用使用 KO 小鼠模型进行体内骨骼增韧。 (3) 验证GAGs强骨的机制作用使用计算方法。目标 2：确定与年龄相关的 GAG/PG 损失及其对与年龄相关的骨骼韧性退化。在这里，我们将使用离体人类尸体骨和体内动物尸体骨模型在三个子目标中检验假设：（1）确定 GAG/PG 对韧性的年龄相关影响使用人类尸体骨样本对两性的皮质骨和小梁骨进行分析。 (2)确定效果使用小鼠骨离体模型研究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 在阻止与年龄相关的 GAG 损失方面的功效并使用衰老大鼠模型维持骨骼的韧性。完成这一目标后，我们期望了解 GAGs/PGs 在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 在阻止年龄相关的 GAG 方面的功效骨骼韧性丧失。这项研究的结果将为与年龄相关的骨质脆性提供重要见解骨折并促进开发预测和预防老年人脆性骨折的新策略人口。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small leucine-rich proteoglycans in physiological and biomechanical function of bone.

DOI：
10.1016/j.mbplus.2021.100063
发表时间：
2021-08
期刊：
Matrix biology plus
影响因子：
0
作者：
Hua R;Jiang JX
通讯作者：
Jiang JX

Removal of glycosaminoglycans affects the in situ mechanical behavior of extrafibrillar matrix in bone.

DOI：
10.1016/j.jmbbm.2021.104766
发表时间：
2021-11
期刊：
Journal of the mechanical behavior of biomedical materials
影响因子：
3.9
作者：
Han Y;Gomez J;Hua R;Xiao P;Gao W;Jiang JX;Wang X
通讯作者：
Wang X

Characterization of Microstructural Changes on Biglycan Induced Mice Bone by Low-Field Nuclear Magnetic Resonance.

DOI：
10.31058/j.ap.2021.42004
发表时间：
2021-06
期刊：
Applied physics (Kowloon, China)
影响因子：
0
作者：
Ni, Qingwen;Hua, Rui;Holland, Douglas;Tinajero, Anahi;Han, Yan;Jiang, Jean X;Wang, Xiaodu
通讯作者：
Wang, Xiaodu

Assessment of glycosaminoglycan content in bone using Raman spectroscopy.

DOI：
10.1016/j.bone.2023.116751
发表时间：
2023-06
期刊：
BONE
影响因子：
4.1
作者：
Heath, Savannah;Han, Yan;Hua, Rui;Roy, Anuradha;Jiang, Jean;Nyman, Jeffry S.;Wang, Xiaodu
通讯作者：
Wang, Xiaodu

Biglycan and chondroitin sulfate play pivotal roles in bone toughness via retaining bound water in bone mineral matrix.