Epigenetic Regulation of Orofacial Bone Homeostasis and Aging by KDM4B

KDM4B 对口面部骨稳态和衰老的表观遗传调控

• 批准号: 9636222
• 负责人: CUN-YU WANG
• 金额: $ 37.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9636222
• 关键词: Adipocytes; Adipose tissue; Affect; Aging; Alveolar; Anatomy; Bone Marrow; Bone Regeneration; Bone Tissue; Bone Transplantation; Calvaria; Cephalic; ChIP-seq; Chondrocytes; Chronic; Connective Tissue; Defect; Dental; Dental Implants; Dental Pulp; Dentin; Disease; Economics; Elderly; Embryo; Epigenetic Process; Estrogens; Femur; Gene Activation; Gene Targeting; Genes; Genetic Transcription; Gingiva; Goals; Histone H3; Homeostasis; Impairment; In Vitro; Inflammation; Joint structure of suture of skull; Knockout Mice; Limb structure; Lysine; Mandible; Marrow; Maxilla; Mediating; Mesenchymal; Mesenchyme; Metabolic; Modeling; Molecular; Multipotent Stem Cells; Mus; Natural regeneration; Neural Crest Cell; Odontoblasts; Osteogenesis; Osteoporosis; PTH gene; Play; Regulation; Role; Site; Small Interfering RNA; Societies; Source; Stem cells; Stromal Cells; Testing; Therapeutic; Tissues; Tooth structure; Transplantation; adult stem cell; alveolar bone; base; beta catenin; bone; bone aging; bone loss; bone mass; craniofacial bone; craniofacial tissue; epigenetic regulation; histone demethylase; hormonal signals; in vivo; in vivo regeneration; injured; innovation; interest; lipid biosynthesis; long bone; novel strategies; oral tissue; orofacial; osteogenic; prevent; public health relevance; reconstruction; recruit; repaired; screening; self-renewal; skeletal; social; stem; stemness; substantia spongiosa; tibia; tissue regeneration; transcriptome sequencing

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.

项目概要/摘要 该应用程序的目标是了解控制的表观遗传和分子机制 口面部骨老化和骨质疏松症与长骨平行，并探讨靶向的程度 表观遗传因素可以预防口面部骨老化并促进牙齿、口腔和颅面部组织 再生。衰老会导致骨骼发生显着变化，其特征是成体干细胞减少 池、自我更新和骨小梁形成，以及骨髓脂肪组织积累的增加。 口面骨，特别是牙槽骨/小梁骨，是一种动态的、自我更新的组织，具有高周转率 率通常随着年龄的增长而急剧下降。间充质干细胞/基质细胞（MSC）是成体干细胞 长骨和口面部骨中的细胞，负责组织的持续更新、再生和修复。 源自口面骨组织（OMSC）的间充质干细胞是颅面骨再生的极好来源 由于它们的胚胎起源更接近受伤部位。过去十年来，取得了重大进展 旨在了解控制骨骼衰老和骨质疏松症的分子机制。然而，很少 了解表观遗传因素如何控制骨骼稳态和衰老，特别是口面部骨 老化。通过 siRNA 筛选，我们发现组蛋白去甲基化酶 KDM4B 在 通过删除赖氨酸 9 (H3K9me3) 处的三甲基化组蛋白 H3 来实现 BMSC 的成骨分化。这 与对照组相比，从衰老小鼠分离的 BMSC 中 Kdm4b 的表达显着下调 年轻的老鼠。为了探索 KDM4B 在口面部骨稳态和衰老中的功能作用，我们利用 Prx1Cre 小鼠删除四肢和颅间质中的 Kdm4b。我们发现KDM4B的删除 通过减少骨形成和增加脂肪生成来加速口面部骨老化和骨质疏松症。 重要的是，我们还发现了甲状旁腺激素（PTH），它已被证明可以调节 MSC 干性和命运决定，在 OMSC 中诱导 Kdm4b。基于这些令人兴奋的研究，我们假设 KDM4B 是控制口面部骨老化和 OMSC 干性的关键表观遗传因子，并且 KDM4B 的诱导促进 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 OMSCs 与 BMSCs 并行的命运决定、成骨和自我更新； 2）判断是否 KDM4B的诱导可防止口面部骨老化并促进体内口面部骨再生 与长骨平行； 3) 探索KDM4B控制口面骨的表观遗传机制 OMSCs 的衰老和自我更新与 BMSCs 并行。我们研究的新发现将具有重要意义 对开发预防口面部骨老化的创新治疗策略的影响 促进颅面骨再生。