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

摘要 颅面骨老化严重影响创伤后骨缺损的修复和再生。 高龄是许多慢性和衰弱骨骼疾病的关键危险因素，包括骨质疏松症 和牙周炎。牙周炎是牙槽骨和牙周结缔组织的炎性破坏， 导致牙齿支撑力的丧失。随着年龄的增长，疾病的易感性和严重性急剧增加， 在老龄化社会中导致了一个重大的公共卫生问题。然而，驱动的机制 颅面部骨骼老化和与年龄相关的牙周炎恶化在很大程度上仍不清楚。 细胞衰老，即衰老和受损细胞的停止增殖，在衰老和损伤的过程中起着重要作用。 相关慢性疾病，包括糖尿病、骨质疏松症和牙周炎。间充质干细胞 具有自我更新能力和多重血统潜力。MSC池因衰老而耗尽 代表着骨骼老化的标志之一。衰老的MSCs失去增殖、自我更新的潜力 成骨分化，导致长骨骨量受损，修复延迟。理学硕士 衰老还与年龄诱导的氧化应激累积、线粒体功能障碍和 DNA损伤。应激诱导的衰老可能通过改变MSC介导的免疫调节 衰老相关分泌表型(SASP)。间充质干细胞之间分子联系的直接证据 缺乏衰老和与年龄相关的颅面骨丢失。值得注意的是，肺泡骨髓来源的MSCs 与长骨MSCs相比，(ABMSCs)更适合于颅面修复，但表现出特定的小生境。 对环境刺激的行为和反应。 过氧化物酶体增殖物激活受体γ共激活因子1α(PGC-1α)是一种转录共激活因子。 在线粒体生物发生和各种富含线粒体的组织中的氧化应激调节中的重要作用。 最近，我们发现pgc-1α直接调节骨髓间充质干细胞的细胞命运决定，以保护骨骼老化。 骨质疏松症。PGC-1α缺失也损害了间充质干细胞的ROS防御，导致氧化应激增加。 然而，PGC-1α在骨髓间充质干细胞衰老和头面部骨骼组织中的作用尚不清楚。基于我们的 初步实验显示，骨髓间充质干细胞特异性缺失PGC-1α显著加重AGE诱导的骨小梁 下颌骨的骨质流失。PGC-1α的整体缺失加剧了大鼠牙周炎和骨丢失 小鼠牙周炎模型。有趣的是，体外分析显示，缺乏pgc-1α会促进复制 骨髓间充质干细胞的衰老。因此，我们假设pGC-1α通过调节 氧化应激对年龄相关的头面部和牙周骨丢失的影响。为了检验我们的假设，我们建议 目的：1)确定前列腺素C-1α是否对骨髓间充质干细胞衰老和颅面骨衰老有调节作用； 2)确定前列腺素C-1α是否调节细胞衰老以影响增龄性牙周骨丢失； 3)阐明PGC-1α调控骨髓间充质干细胞衰老的分子机制。

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.