Age-related Control of Bone Quality by Osteocyte TGF-beta Signaling

骨细胞 TGF-β 信号对骨质量的年龄相关控制

• 批准号: 10219148
• 负责人: Charles August Schurman
• 金额: $ 2.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219148
• 关键词: 3-Dimensional; Advanced Glycosylation End Products; Affect; Age; Age-Related Bone Loss; Aging; Architecture; Behavior; Biochemical; Biocompatible Materials; Biological; Biological Assay; Bone Matrix; Bone remodeling; Bone structure; Chemicals; Clinical; Collagen; Data; Defect; Elderly; Enzyme-Linked Immunosorbent Assay; Etiology; Exhibits; Extracellular Matrix; Fracture; Gene Expression; Genes; Genetic Epistasis; Health; Human; Impairment; In Situ; Individual; Knowledge; Lead; Ligands; Link; Maintenance; Matrix Metalloproteinases; Mechanics; Mediating; Minerals; Modeling; Modification; Molecular; Mus; Musculoskeletal; Osteocytes; Outcome; Performance; Periodicity; Phenotype; Population; Process; Property; Regulation; Repression; Resistance; Roentgen Rays; Role; Signal Pathway; Signal Transduction; Slide; Stress; Synchrotrons; Techniques; Testing; Time; Tissues; Transforming Growth Factor beta; age effect; age related; aged; base; bone; bone aging; bone cell; bone fragility; bone health; bone loss; bone mass; bone quality; bone strength; bone toughness; confocal imaging; cortical bone; crosslink; digital imaging; experimental study; flexibility; inhibitor/antagonist; insight; mechanical behavior; member; mouse model; nanoscale; prevent; therapeutic development; therapeutic target; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Bone strength relies on bone mass and bone quality. However, in over half of fracture cases in elderly populations, deficits in bone mass are not implicated. In these cases, it is believed that components of bone quality, including bone material properties and nanoscale material performance, degenerate with age. Cellular mechanisms controlling bone quantity are well defined, but mechanisms regulating bone quality are less well understood. Transforming growth factor beta (TGFb) is one of the known regulators of bone quality through its control of osteocyte-mediated perilacunar/canalicular remodeling (PLR). TGFb regulated expression of MMP13 in osteocytes is a critical aspect of PLR allowing the active remodeling of the bone extracellular matrix (ECM). Absence of this activity, as seen in mice with an osteocyte-specific disruption of TGFb signaling (TbRIIocy-/-), results in decreased MMP13 expression, disruption to the osteocyte lacunar canalicular network (LCN), and low bone toughness despite any significant loss in cortical bone mass. However, the extent to which the loss of PLR contributes to age related bone fragility remains unstudied and represents a significant gap in knowledge toward the regulation of bone quality with age. Previous studies reveal similarities between the material behavior of aged bone and that of bone with impaired TGFb signaling. Both exhibit embrittlement, seen by a lack of extrinsic toughening mechanisms such as crack deflection, as well as decreases to macroscale material properties. Both demonstrate a disorganization of the LCN. Additionally, aged bone accumulates large amounts of non-enzymatic crosslinks to the bone ECM in the form of Advanced Glycation End products (AGEs). These crosslinks have been proposed as a direct molecular impairment responsible for bone embrittlement with age. Data from RNAseq shows significantly decreased MMP expression in aged mouse bone, implying a lack of PLR in aged bone for the first time. Collectively, these data suggest a causal link between PLR and the poor bone quality in both aged bone and TGFb deficient bone. This proposal tests the causality between these two models of degenerated bone quality. This project will test the hypothesis that osteocyte PLR is sensitive to declining TGFb activity in bone with age and that this contributes to declining BQ over a lifetime. Aim 1 will evaluate similarities between the biological mechanisms controlling bone quality in aging and TbRIIocy-/- bone. Aim 2 will utilize synchrotron x-ray experiments to confirm if nanoscale deformation mechanics in TbRIIocy-/- bone are conserved from studies on aging bone to connect these models on the nanoscale. Aim 3 will attempt a rescue of age degenerated bone quality by limiting the activity of the TGFb signaling inhibitor Smad7 specifically within osteocytes to revitalize PLR and bone quality in aged mice. This study will investigate if osteocytes are the cellular players responsible for the age-related loss of bone quality and provide a therapeutic target for a currently unaddressed clinical need.

项目摘要/摘要 骨骼强度依赖于骨骼质量和骨骼质量。但是，在老年人中超过一半的骨折病例中 种群，骨骼质量的缺陷并不涉及。在这些情况下，人们认为骨骼的成分 质量，包括骨骼材料特性和纳米级材料性能，随着年龄的增长而退化。 控制骨骼数量的细胞机制定义得很好，但是调节骨骼质量的机制 不太了解。转化生长因子β（TGFB）是骨质质量的已知调节因子之一 通过控制骨细胞介导的Perilacunar/口管重塑（PLR）。 TGFB调节表达 骨细胞中的MMP13是PLR的关键方面，允许骨外基质的主动重塑 （ECM）。缺乏这种活性，如在TGFB信号转导的骨细胞特异性破坏的小鼠中所见 （tbriiocy - / - ），导致MMP13表达降低，破坏骨细胞lacunar管网络 （LCN）和低骨韧性，尽管皮质骨骼质量有显着损失。但是，在多大程度上 PLR的丧失导致与年龄相关的骨骼脆弱性造成了尚未研究，并且代表了一个显着的差距 了解随着年龄的增长来调节骨骼质量的知识。 先前的研究揭示了老化骨的材料行为与骨的材料行为与 TGFB信号受损。两者都表现出脆弱，由于缺乏外在的韧性机制 作为裂纹挠度，并降低了宏观材料的特性。两者都表现出混乱 LCN。此外，老化的骨会积聚大量的非酶联交联向骨ECM 以先进的糖基化终产物（年龄）的形式。这些交叉链接已被提出为直接 分子损伤导致年龄造成骨骼脆化。来自RNASEQ的数据显示出明显的 老年小鼠骨的MMP表达降低，这意味着第一次缺乏老年骨骼的PLR。 总的来说，这些数据表明PLR与老年骨骼和骨质差之间存在因果关系 TGFB缺乏骨头。该建议测试了这两种退化的骨质质量模型之间的因果关系。 该项目将检验以下假设：骨细胞PLR对骨骼中的TGFB活性下降敏感 年龄，这有助于一生中的BQ下降。 AIM 1将评估生物学之间的相似性 控制老化和tbriiocy骨质量的机制 - / - 骨。 AIM 2将利用同步加速器X射线实验 为了确认Tbriiocy-/ - 骨中的纳米级变形力学是否是从衰老骨骼到 在纳米级上连接这些模型。 AIM 3将尝试通过限制年龄退化的骨质质量 TGFB信号抑制剂SMAD7的活性专门在骨细胞中振兴PLR和骨骼质量 在老年小鼠中。这项研究将调查骨细胞是否是导致与年龄相关的损失的细胞参与者 骨质质量，为当前未解决的临床需求提供了治疗靶标。