Regulation of Alveolar Bone Marrow MSC Senescence in Skeletal Aging and Periodontitis

骨骼衰老和牙周炎中牙槽骨髓 MSC 衰老的调节

基本信息

批准号：
10621947
负责人：
Bo Yu
金额：
$ 37.05万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-02 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621947
关键词：
Acetylcysteine Adult Age Age-Related Bone Loss Aging Alveolar Bone Loss American Antioxidants B-Cell Activation Behavior Biogenesis Biological Assay Bone Marrow Bone remodeling Cell Aging Cell Lineage Cell Respiration Cell Separation Cells Chronic Chronic Disease Connective Tissue DNA Damage Defect Diabetes Mellitus Disease susceptibility Elderly Exhibits Goals Impaired healing Impairment In Vitro Inflammation Inflammatory Link Mandible Mediating Mesenchymal Stem Cells Mitochondria Mitochondrial DNA Modeling Molecular Morbidity - disease rate Mus Natural regeneration Osteoblasts Osteoporosis Ovariectomy Oxidative Regulation Oxidative Stress PPAR gamma Periodontitis Phenotype Play Prevalence Process Production Proliferating Public Health Quercetin Reactive Oxygen Species Regulation Rejuvenation Risk Factors Role SIRT1 gene Severities Severity of illness Signal Transduction Skeleton Societies Stimulus Stress Testing Therapeutic Tissues Tooth Loss Transcription Coactivator Transcriptional Activation Transcriptional Regulation Trauma age group age related aged aging population alveolar bone alveolar destruction antioxidant enzyme bone aging bone loss bone marrow mesenchymal stem cell bone mass cell age cell injury craniofacial craniofacial bone craniofacial repair diacetyldichlorofluorescein exhaustion experimental study fragility fracture immunoregulation in vitro Assay in vivo inflammatory bone loss interest long bone mitochondrial dysfunction mortality novel older patient osteogenic overexpression oxidative damage proliferation potential regeneration potential repaired response self-renewal senescence skeletal skeletal disorder skeletal tissue stem cell aging stem cells substantia spongiosa

项目摘要

ABSTRACT Aged craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects. Advanced age is a critical risk factor for many chronic and debilitating skeletal diseases including osteoporosis and periodontitis. Periodontitis is the inflammatory destruction of alveolar bone and periodontal connective tissue, resulting in the loss of tooth support. The disease susceptibility and severity increase dramatically with age, leading to a significant public health concern in the aging society. However, the mechanisms that drive craniofacial skeletal aging and age-related exacerbation of periodontitis remain largely unknown. Cellular senescence, the halting of proliferation for aged and damaged cells, play an important role in age- related chronic diseases including diabetes, osteoporosis and periodontitis. Mesenchymal stem cells (MSCs) possess self-renewal ability and multiple lineage potentials. Exhaustion of the MSC pool through senescence represents one of the hall marks for skeletal aging. Senescent MSCs lose potential for proliferation, self-renewal and osteogenic differentiation, contributing to the impaired bone mass and delayed repair in long-bone. MSC senescence is also associated with age-induced acculumation of oxidative stress, mitochondrial dysfunction and DNA damage. The stress-induced senescence could alter MSC-mediated immunomodulation through senescence-associated secretory phenotype (SASP). The direct evidence on the molecular link between MSC senescence and age-related craniofacial bone loss is lacking. Notably, alveolar bone marrow derived MSCs (aBMSCs), compared to long-bone MSCs, are more suitable for craniofacial repair, but exhibit niche-specific behaviors and responses to environmental stimuli. Peroxisome proliferator-activated receptor γ coactivators 1α (PGC-1α) is a transcriptional coactivator with essential roles in mitochondrial biogenesis and regulation of oxidative stress in various mitochondria-rich tissues. Recently, we found that PGC-1α directly regulates cell fate decisions of MSCs to protect against skeletal aging and osteoporosis. PGC-1α depletion also impaired ROS defense in MSCs, resulting in increased oxidative stress. However, the role of PGC-1α in MSC senescence and craniofacial skeletal tissue is unknown. Based on our preliminary experiments, MSC-specific depletion of PGC-1α significantly exacerbated age-induced trabecular bone loss in the mandible. Global depletion of PGC-1α exacerbated periodontal inflammation and bone loss in murine periodontitis models. Intriguingly, in vitro assays revealed that lack of PGC-1α promoted replicative senescence of aBMSCs. Thus, we hypothesize that PGC-1α modulates aBMSC senescence via regulation of oxidative stress to impact age-related craniofacial and periodontal bone loss. To test our hypothesis, we propose the following aims:1) To determine if PGC-1α regulates senescence of aBMSCs and craniofacial skeletal aging; 2) To determine if PGC-1α regulates cellular senescence to influence age-exacerbated periodontal bone loss; 3) To elucidate the underlying molecular mechanism of how PGC-1α modulates aBMSC senescence.

抽象的老化的颅面部骨骼显着损害创伤引起的骨缺损的修复和再生。高龄是许多慢性和衰弱性骨骼疾病（包括骨质疏松症）的关键危险因素牙周炎是牙槽骨和牙周结缔组织的炎症破坏，导致牙齿支持的丧失，疾病的易感性和严重程度随着年龄的增长而急剧增加，导致老龄化社会的重大公共卫生问题然而，驱动机制。颅面骨骼老化和年龄相关的牙周炎恶化仍然很大程度上未知。细胞衰老，即衰老和受损细胞增殖的停止，在衰老过程中发挥着重要作用。相关慢性疾病包括糖尿病、骨质疏松症和牙周炎。具有自我更新能力和多种谱系潜力，通过衰老耗尽 MSC 库。代表骨骼老化的标志之一，衰老的间充质干细胞失去增殖和自我更新的潜力。和成骨分化，导致骨量受损和长骨修复延迟。衰老还与年龄引起的氧化应激积累、线粒体功能障碍和 DNA损伤可能通过改变MSC介导的免疫调节。衰老相关分泌表型（SASP） MSC 之间分子联系的直接证据。衰老和与年龄相关的颅面骨丢失值得注意的是，牙槽骨髓来源的 MSC 缺乏。 (aBMSC) 与长骨 MSC 相比，更适合颅面修复，但表现出利基特异性行为和对环境刺激的反应。过氧化物酶体增殖物激活受体 γ 共激活剂 1α (PGC-1α) 是一种转录共激活剂在线粒体生物发生和各种富含线粒体的组织中氧化应激的调节中发挥重要作用。最近，我们发现PGC-1α直接调节MSCs的细胞命运决定，以防止骨骼衰老 PGC-1α 耗竭也会损害 MSC 中的 ROS 防御，导致氧化应激增加。然而，根据我们的研究，PGC-1α 在 MSC 衰老和颅面骨骼组织中的作用尚不清楚。初步实验显示，MSC 特异性 PGC-1α 耗竭显着加剧了年龄引起的小梁下颌骨骨质流失加剧了牙周炎症和骨质流失。有趣的是，体外试验表明缺乏 PGC-1α 可以促进复制。因此，我们研究 PGC-1α 通过调节 aBMSC 的衰老。氧化应激影响与年龄相关的颅面和牙周骨质流失为了检验我们的假设，我们提出。目的如下：1）确定PGC-1α是否调节aBMSCs的衰老和颅面骨骼衰老； 2) 确定PGC-1α是否通过调节细胞衰老来影响年龄加剧的牙周骨丢失； 3) 阐明PGC-1α如何调节aBMSC衰老的潜在分子机制。