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.

抽象的老化的颅面骨骼严重损害了创伤引起的粘结缺陷的修复和再生。高龄是许多慢性和使人衰弱的骨骼疾病在内的关键危险因素和牙周炎。牙周炎是肺泡骨和牙周连接组织的炎症破坏，导致牙齿支撑丧失。随着年龄的增长，疾病的敏感性和严重程度急剧增加，导致衰老社会的公共卫生关注。但是，驱动的机制颅面骨骼老化和与年龄有关的牙周炎的加重仍然未知。细胞感应，年龄和受损细胞的增殖停止，在年龄中起重要作用相关的慢性疾病，包括糖尿病，骨质疏松症和牙周炎。间充质干细胞（MSC）具有自我更新能力和多个谱系潜力。通过感应耗尽MSC池代表了骨骼老化的大厅标记之一。衰老的MSC失去了增殖的潜力，自我更新和成骨分化，导致骨骼质量受损和长骨修复延迟。 MSC 感应还与年龄诱导的氧化应激，线粒体功能障碍和 DNA损伤。应力诱导的感应可以通过MSC介导的免疫调节感应相关的秘书表型（SASP）。关于MSC之间分子联系的直接证据缺乏衰老和与年龄有关的颅面骨质流失。值得注意的是，牙槽骨骨髓衍生的MSC （ABMSC）与长骨MSC相比，更适合颅面修复行为和对环境刺激的反应。过氧化物体增生剂激活受体γ共激活因子1α（PGC-1α）是一种转录共激活因子，与在各种线粒体组织中的线粒体生物发生和氧化应激调节中的重要作用。最近，我们发现PGC-1α直接调节MSC的细胞脂肪决策以防止骨骼老化和骨质疏松症。 PGC-1α的耗竭也损害了MSC中ROS防御，从而导致氧化应激增加。然而，PGC-1α在MSC感应和颅面骨骼组织中的作用尚不清楚。基于我们初步实验，PGC-1α的MSC特异性耗竭显着加剧了年龄引起的小梁下颌骨的骨质流失。 PGC-1α的全球耗竭加剧了牙周注射和骨质流失鼠牙周炎模型。有趣的是，体外测定表明缺乏PGC-1α促进了复制 ABMSC的感应。这，我们假设PGC-1α通过调节氧化应激会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，我们提出以下目的：1）确定PGC-1α是否调节ABMSC和颅面骨骼老化的感应； 2）确定PGC-1α是否调节细胞感应以影响年龄效果的牙周骨质流失； 3）阐明了PGC-1α如何调节ABMSC感应的基本分子机制。