Post-Transcriptional Control of Aging-Associated Inflammation and Bone Homeostasis

摘要 随着年龄的增长，免疫系统会经历动态变化，其特征是 获得性免疫和低级别慢性炎症的激活。这种炎症的慢性激活 与衰老或“发炎”有关。Tristetraprolin(TTP)是一种RNA结合蛋白，可在翻译后 与靶mRNAs(包括关键的促炎mRNAs)3‘-非编码区富含腺苷酸尿苷的元件结合 如肿瘤坏死因子α、环氧合酶-2和白介素6)，以促进其快速周转。重要的是，我们最近证明了 未能在转录后水平调节细胞因子的表达会导致慢性炎症和 与年龄/性别匹配的对照组相比，TTP-/-小鼠的自发性牙槽骨丢失随年龄增长而减少。因此，TTP 在年龄相关的方式中，牙槽骨的表达似乎对牙槽骨的动态平衡是必不可少的。我们的预赛 本申请中的数据和最近发表的数据有力地支持了巨噬细胞和髓系细胞- 在TTP-/-小鼠中，衍生抑制细胞(MDSC)群体随着年龄的增长而扩大，并伴随着减少 在淋巴细胞群体中。综上所述，我们的结果支持了TTP可能是一个关键的内在因素的观点 炎症因子和髓系扩增/分化对骨骼的贡献 动态平衡。我们建议检验TTP控制炎症并影响牙槽骨和牙槽骨的假设 长骨骨骼健康随年龄增长。该提案的具体目的是：1)定义髓系衍生细胞的作用 TTP对随年龄增长的骨稳态的影响；2)确定TTP改变破骨细胞生成的机制 随着年龄的增长；以及3)确定在健康衰老过程中，TTP表达增加是否会改变骨重建。在 这些研究的结论，将为未来的研究提供关于TTP的新见解 有可能成为口腔和非口腔骨骼组织健康老化的治疗靶点。

ABSTRACT With advancing age, the immune system undergoes dynamic changes characterized by both impairment of adaptive immunity and activation of low-grade chronic inflammation. This chronic activation of inflammation associated with aging or `inflammaging'. Tristetraprolin (TTP) is an RNA binding proteins that post-translationally bind to adenylate-uridylate–rich elements in the 3′-UTR of target mRNAs (including key pro-inflammatory mRNAs e.g. TNFα, COX-2 and IL-6) to promote their rapid turnover. Importantly, we have recently demonstrated that failure to regulate expression of cytokines at the posttranscriptional level contributes to chronic inflammation and spontaneous alveolar bone loss with age in TTP-/- mice compared to age/sex match controls. Thus, TTP expression appears to be essential for alveolar bone homeostasis in an age-dependent manner. Our preliminary data in this application and recently published data strongly support the concept that macrophages and myeloid- derived suppressor cell (MDSC) populations are expanded with age in TTP-/- mice, with concomitant reduction in lymphocyte populations. Taken together, our results support that notion that TTP may be a critical intrinsic factor of inflammaging and myeloid lineage expansion/differentiation that contributes towards skeletal homeostasis. We propose to test the hypothesis that TTP controls inflammaging and impacts alveolar bone and long bone skeletal health with age. The specific aims of the proposal are: 1) define the role of myeloid-derived TTP on bone homeostasis with age; 2) determine the mechanisms that TTP uses to alter osteoclastogenesis with age; and 3) Establish if increased TTP expression alters bone remodeling during healthy aging. At the conclusion of these studies, new insights regarding TTP will be provided for future studies where would be potentially a therapeutic target for healthy aging of the oral and non-oral skeletal tissues.