Epigenetic Regulation of Orofacial Bone Homeostasis and Aging by KDM4B

项目摘要/摘要 这个应用程序的目标是了解控制 颌面部骨质老化和骨质疏松症与长骨并行，并探讨靶向的程度 表观遗传因子可防止口腔面骨老化，促进牙齿、口腔和颅面组织的生长 再生。衰老引起骨骼的显著变化，其特征是成人干细胞减少。 骨池、自我更新和骨小梁形成，以及增加骨髓脂肪组织积聚。 口腔颌面骨，尤其是牙槽骨/松质骨，是一种动态、自我更新、高转换率的组织。 这一比率往往随着年龄的增长而急剧下降。间充质干细胞/基质细胞是成体干细胞。 长骨和口腔面骨中的细胞，负责持续的组织更新、再生和修复。 口面部骨组织来源的MSCs是颅面骨再生的良好来源 因为它们的胚胎起源更接近受伤部位。在过去的十年中，取得了重大进展 在理解骨骼老化和骨质疏松症的分子机制方面取得了进展。然而，几乎没有 已知表观遗传因素如何控制骨骼的动态平衡和衰老，特别是口腔颌面部骨骼 衰老。通过siRNA筛选，我们发现组蛋白去甲基酶KDM4B在 赖氨酸9(H3K9me3)消除组蛋白H3三甲基化诱导骨髓间充质干细胞向成骨分化这个 Kdm4b在衰老小鼠分离的BMSCs中的表达显著下调 幼小的老鼠。为了探索KDM4B在口腔面部骨骼动态平衡和衰老中的功能作用，我们利用 Prx1Cre小鼠删除肢体和颅骨间充质中的Kdm4b。我们发现KDM4B的缺失 通过减少骨形成和增加脂肪生成来加速口腔面骨老化和骨质疏松。 重要的是，我们还鉴定了甲状旁腺激素(PTH)，它已被证明调节MSC 在OMSCs中诱导Kdm4b。基于这些令人兴奋的研究，我们假设 KDM4B是控制口腔面骨老化和OMSC干性的关键表观遗传因子，以及 KDM4B的诱导可促进OMSC介导的颅面骨再生。为了检验我们的假设，我们 提出以下三个具体目标：1)确定KDM4B是否在监管中发挥关键作用 与BMSCs并行的OMSCs的命运决定、成骨和自我更新的研究；2)确定 KDM4B的诱导抑制口腔颌面骨衰老并促进口腔颌面骨再生 与长骨平行；3)探讨KDM4B控制口腔面骨的表观遗传机制 OMSCs与BMSCs并存的衰老和自我更新我们研究的新发现将具有重要的意义 发展创新的治疗策略以预防口腔颌面部骨老化和 促进颅面骨再生。

Project Summary/Abstract The goals of this application are to understand the epigenetic and molecular mechanisms that control orofacial bone aging and osteoporosis in parallel with long bones and explore the extent to which targeting epigenetic factor could prevent orofacial bone aging and promote dental, oral and craniofacial tissue regeneration. Aging causes significant changes to bone, characterized by a decrease in the adult stem cell pool, self-renewal and trabecular bone formation, and an increase in marrow adipose tissue accumulation. Orofacial bone, especially alveolar/trabecular bone, is a dynamic and self-renewing tissue with high turnover rate which often dramatically decreases with aging. Mesenchymal stem/stromal cells (MSCs) are adult stem cells in long and orofacial bones and are responsible for continuous tissue renewal, regeneration, and repair. MSCs derived from orofacial bone tissues (OMSCs) are excellent sources for craniofacial bone regeneration due to their closer embryonic origins to the injured sites. Over the past decade, significant progress has been made in understanding the molecular mechanisms governing skeletal aging and osteoporosis. However, little is known about how epigenetic factors control skeletal homeostasis and aging, specifically orofacial bone aging. Using siRNA screening, we discovered that the histone demethylase KDM4B played a critical role in osteogenic differentiation of BMSCs by erasing trimethylated histone H3 at lysine 9 (H3K9me3). The expression of Kdm4b was significantly downregulated in BMSCs isolated from aging mice compared to young mice. To explore the functional role of KDM4B in orofacial bone homeostasis and aging, we utilized Prx1Cre mice to delete Kdm4b in limb and cranial mesenchyme. We found that the deletion of KDM4B accelerated orofacial bone aging and osteoporosis by reducing bone formation and increasing adipogenesis. Importantly, we also identified that parathyroid hormone (PTH), which has been showed to regulate MSC stemness and fate decision, induced Kdm4b in OMSCs. Based on these exciting studies, we hypothesize that KDM4B is a critical epigenetic factor which controls orofacial bone aging and OMSC stemness, and induction of KDM4B promotes OMSC-mediated craniofacial bone regeneration. To test our hypothesis, we propose the following three specific aims: 1) To determine whether KDM4B plays a critical role in regulation of fate decision, osteogenesis and self-renewal of OMSCs in parallel with BMSCs; 2) To determine whether induction of KDM4B prevents orofacial bone aging and promotes orofacial bone regeneration in vivo in parallel with long bones; and 3) To explore epigenetic mechanisms by which KDM4B controls orofacial bone aging and self-renewal of OMSCs in parallel with BMSCs. New findings from our studies will have important implications in developing innovative therapeutic strategies for preventing orofacial bone aging and promoting craniofacial bone regeneration.