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.

项目摘要/摘要 该应用的目标是了解控制的表观遗传和分子机制 与长骨平行的口面骨老化和骨质疏松症，并探索靶向的程度 表观遗传因子可以预防牙骨老化，并促进牙齿，口腔和颅面组织 再生。衰老会引起骨骼的重大变化，其特征是成年干细胞的减少 池，自我更新和小梁骨形成，以及骨髓脂肪组织积累的增加。 口面骨，尤其是肺泡/小梁骨，是一种动态和自我更新的组织 速率通常会随着衰老而大大降低。间充质干/基质细胞（MSC）是成人茎 长长和口面骨的细胞，负责连续的组织更新，再生和修复。 源自口面骨组织（OMSC）的MSC是颅面再生的极好来源 由于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 在理解有关骨骼衰老和骨质疏松症的分子机制方面。但是，很少 已经知道表观遗传因素如何控制骨骼稳态和衰老，特别是口面骨 老化。使用siRNA筛选，我们发现组蛋白脱甲基酶KDM4B在 通过在赖氨酸9（H3K9ME3）上擦除三甲基化组蛋白H3的BMSC的成骨分化。这 与从衰老小鼠分离的BMSC中，KDM4B的表达显着下调 年轻的老鼠。为了探索KDM4B在口面骨体内平衡和衰老中的功能作用，我们利用了 PRX1CRE小鼠在肢体和颅间质中删除KDM4B。我们发现删除KDM4B 通过减少骨形成并增加脂肪形成，加速了口腔老化和骨质疏松症。 重要的是，我们还确定了甲状旁腺激素（PTH），该激素已显示为调节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是控制口腔老化和OMSC茎的关键表观遗传因素，并且 KDM4B的诱导促进了OMSC介导的颅面骨再生。为了检验我们的假设，我们 提出以下三个特定目的：1）确定KDM4B是否在调节中起关键作用 与BMSC并行的OMSC的命运决策，成骨和自我更新； 2）确定是否 KDM4B的诱导可防止类似骨老化，并在体内促进体体骨再生 与长骨平行； 3）探索KDM4B控制口面骨的表观遗传机制 与BMSC并行的OMSC老化和自我更新。我们研究的新发现将具有重要的 在制定创新的治疗策略中的影响 促进颅面骨再生。