Morandini A C, Dawson S, Paladines N, Adams N, Ramos-Junior E S
Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA.
Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA.
Cells. 2025 Aug 16;14(16):1266. doi: 10.3390/cells14161266.
Adenosine signaling plays protective roles in gingival mitochondrial health and inflammation control, with the ectoenzyme CD73 implicated in periodontitis. Here, we investigated the effects of selective adenosine A2a receptor (A2aR) stimulation using the agonist CGS21680 in a mouse model of ligature-induced periodontitis (LIP) and in gingival fibroblast mitochondrial function. Mature C57Bl/6 mice underwent LIP and received daily intraperitoneal injections of CGS21680 (0.1 mg/Kg) or saline. After 8 days, gingival tissues and maxillae were analyzed for alveolar bone loss and Il-1β levels. In parallel, murine gingival fibroblasts (mGFs) were treated with Tnf-α (5 ng/mL) ± CGS21680 (10 µM) to assess mitochondrial function, morphology, and quality control. A2aR activation significantly reduced alveolar bone loss and Il-1β expression in vivo. In vitro, CGS21680 suppressed Tnf-α-induced Cxcl10 and Cxcl12 expressions and enhanced Vegf production. Mitochondrial analysis revealed increased mitochondrial complex levels, membrane potential, and mass, alongside reduced reactive oxygen species (ROS), proton leak, and mitochondrial stress. Ultrastructural studies showed elongated, healthier mitochondria and increased pro-fusion markers, indicating enhanced mitochondrial quality control. Overall, A2aR stimulation attenuates periodontal inflammation and confers mitoprotective effects on gingival fibroblasts, supporting its potential as a therapeutic strategy to both mitigate periodontitis progression and preserve tissue bioenergetics supporting cellular resilience.
腺苷信号传导在牙龈线粒体健康和炎症控制中发挥保护作用，胞外酶CD73与牙周炎有关。在此，我们研究了使用激动剂CGS21680选择性刺激腺苷A2a受体（A2aR）在结扎诱导的牙周炎（LIP）小鼠模型和牙龈成纤维细胞线粒体功能中的作用。成熟的C57Bl/6小鼠接受LIP手术，并每天腹腔注射CGS21680（0.1mg/Kg）或生理盐水。8天后，分析牙龈组织和上颌骨的牙槽骨丢失和Il-1β水平。同时，用Tnf-α（5ng/mL）±CGS21680（10µM）处理小鼠牙龈成纤维细胞（mGFs），以评估线粒体功能、形态和质量控制。A2aR激活在体内显著减少牙槽骨丢失和Il-1β表达。在体外，CGS21680抑制Tnf-α诱导的Cxcl10和Cxcl12表达，并增强Vegf产生。线粒体分析显示线粒体复合物水平、膜电位和质量增加，同时活性氧（ROS）、质子泄漏和线粒体应激减少。超微结构研究显示线粒体延长、更健康，且促融合标记物增加，表明线粒体质量控制增强。总体而言，A2aR刺激可减轻牙周炎症，并对牙龈成纤维细胞具有线粒体保护作用，支持其作为一种治疗策略的潜力，既能减轻牙周炎进展，又能维持支持细胞弹性的组织生物能量学。
