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: 10021392
• 负责人: Charles August Schurman
• 金额: $ 3.77万
• 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 2022-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021392
• 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; 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; 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.

项目总结/摘要 骨强度依赖于骨量和骨质量。然而，在超过一半的老年骨折病例中， 人群中，骨量不足不受影响。在这些情况下，据信骨的成分 质量，包括骨材料性质和纳米材料性能，随着年龄的增长而退化。 控制骨量的细胞机制已明确，但调节骨质量的机制 不太被理解。转化生长因子β（TGF β）是已知的骨质量调节因子之一 通过其控制骨细胞介导的骨腔/小管重塑（PLR）。TGF β调节表达 骨细胞中MMP 13的表达是PLR的一个关键方面，允许骨细胞外基质的主动重塑 （ECM）的指令集。缺乏这种活性，如在具有TGF β信号传导的骨细胞特异性破坏的小鼠中所见 （TbRIIocy-/-），导致MMP 13表达降低，骨细胞腔隙小管网络破坏 (LCN)和低骨韧性，尽管皮质骨质量有任何显著损失。然而，在多大程度上 PLR的丧失导致与年龄相关的骨脆性，这一点尚未得到研究， 了解随着年龄增长骨质量的调节。 以前的研究揭示了老年骨和骨的材料行为之间的相似性， TGF β信号传导受损。两者都表现出脆化，表现为缺乏外在增韧机制， 作为裂纹偏转，以及降低到宏观尺度的材料性能。两者都表现出一种无组织性 在LCN。此外，老化的骨积累了大量的非酶交联到骨ECM 晚期糖基化终产物（Advanced Glycation End Products，AGEs）这些交叉连接已被提议作为一种直接的 导致骨随年龄增长而脆化的分子损伤。来自RNAseq的数据显示， 降低老年小鼠骨中MMP的表达，首次提示老年骨中PLR的缺乏。 总的来说，这些数据表明PLR与老年骨和老年人骨质量差之间存在因果关系。 TGFb缺乏的骨骼。该提案测试了这两种骨质退化模型之间的因果关系。 本项目将检验骨细胞PLR对骨中TGF β活性下降敏感的假设， 年龄，这有助于一生中BQ的下降。目标1将评估生物学之间的相似性 控制老化和TbRIIocy-/-骨中的骨质量的机制。AIM 2将利用同步加速器X射线实验 以确认TbRIIocy-/-骨中的纳米级变形力学是否从对老化骨的研究中保留， 在纳米尺度上连接这些模型。目的3将尝试通过限制骨密度来挽救年龄退化的骨质。 TGF β信号传导抑制剂Smad 7在骨细胞内特异性地激活PLR和骨质量的活性 老年小鼠这项研究将调查骨细胞是否是负责与年龄相关的损失的细胞球员 并为目前尚未解决的临床需求提供治疗靶点。