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: 9910063
• 负责人: Charles August Schurman
• 金额: $ 3.68万
• 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/9910063
• 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; Image Analysis; 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/文摘