Osteoblasts Role in Dysfunction of Body Adiposity and Bone Metabolism

成骨细胞在身体肥胖和骨代谢功能障碍中的作用

• 批准号: 10255860
• 负责人: Amjad Javed
• 金额: $ 39.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255860
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Age; Aging; Biochemical; Biology; Biomechanics; Bone Density; Bone Development; Bone Marrow; Bone Marrow Cells; Bone Matrix; Bone Tissue; Brown Fat; Cells; Cessation of life; Chondrocytes; Clinical; Collagen; Data; Diabetes Mellitus; Digestion; Disease; Eating; Embryo; Endocrine; Endocrine Glands; Energy Metabolism; Excision; Exhibits; Failure; Fatty Liver; Fatty acid glycerol esters; Fracture; Functional disorder; Genes; Genetic Transcription; Gonadal structure; Growth; Health Benefit; Hematopoiesis; Homeostasis; Impairment; Incidence; Individual; Insulin; Intervention; Ions; Kidney; Knockout Mice; Lead; Lipodystrophy; Maintenance; Marrow; Mesenchymal; Metabolic; Metabolic Diseases; Metabolism; Minerals; Molecular; Molecular Biology; Mutant Strains Mice; Obesity; Organ; Osteoblasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Pancreas; Pathway interactions; Patients; Peripheral; Phenotype; Physiologic Ossification; Physiology; Premature aging syndrome; Publishing; Regulation; Role; Runx2 protein; Serum; Signal Transduction; Site; Skeleton; Solid; Testing; Therapeutic Intervention; Thermogenesis; Tissues; Transgenic Model; Visceral; adipokines; base; bone; bone aging; bone mass; bone metabolism; bone preservation; calcium phosphate; comorbidity; fracture risk; glucose metabolism; high risk; in vivo; insight; interdisciplinary approach; lipid biosynthesis; mouse model; mutant; novel; novel therapeutics; osteoblast differentiation; osteoporotic bone; paracrine; postnatal; prevent; progenitor; protein purification; skeletal; skeletogenesis; stem cells; transcription factor

ABSTRACT: Patients with metabolic diseases, such as obesity, diabetes, and lipodystrophy exhibit altered bone and fat mass, fat distribution, and energy homeostasis. The underlying mechanisms involved in these dysregulations are poorly understood. Bone and fat tissue are both endocrine organs and secrete factors that regulate energy metabolism. Bone synthesizing osteoblasts and fat forming adipocytes are derived from common mesenchymal progenitors. Increased bone marrow fat and decreased bone mass is noted in osteoporosis, diabetes, and aging. Osteoporotic bones at highest risk for a fracture always exhibit increased marrow fat. These clinical observations suggest that targeting bone marrow fat may be a treatment for these diseases and for 2-million fractures in US adults that occur yearly due to osteoporosis and low bone mass. However, the origin and function of the bone marrow fat, as well as its relationship to the bone and other peripheral fat depots are not very clear. The bone marrow fat is a unique fat depot that is located adjacent to the bone and is different from either white or brown adipose tissue. In this study, we aim to identify molecular mechanisms underlying the metabolic diseases with comorbidity of the bone and fat, especially novel factors secreted by the osteoblast and osteocytes that can regulate marrow adipogenesis, peripheral fat distribution, energy homeostasis and maintenance of adult bone mass. The Runx2 transcription factor is essential for the commitment of mesenchymal progenitors to the cells of skeletal lineage. Global null mice of the Runx2 gene are embryonic lethal due to complete loss of osteoblast differentiation and bone formation. We have recently published that Runx2 is also essential for chondrocyte proliferation, hypertrophic maturation, and endochondral ossification. Our preliminary data show that selective deficiency of Runx2 in mature osteoblasts and osteocytes inhibits postnatal bone synthesis and trigger a rapid onset of osteoporosis, premature aging, and death. Runx2 activity inhibits commitment of mesenchymal cells to the adipocyte lineage. Deletion of Runx2 in osteoblasts/osteocytes results in the near absence of visceral adiposity but a dramatic increase in marrow adipogenesis. We further demonstrate that Runx2 blocks adipogenesis by altering energy metabolism and by inhibiting critical signaling from Akt and Erk in the insulin pathways. Based on the preliminary data we hypothesize that Runx2 regulated signals from mature osteoblast and osteocytes control marrow adipogenesis, peripheral fat distribution, and energy homeostasis. We will utilize novel mouse models to test our hypotheses in three specific aims. Aim 1 will examine the role of Runx2 deficient osteoblasts and osteocytes in the reciprocal maintenance of adult fat and bone mass. Aim 2 will test the requirement of osteoblast/osteocyte for marrow and peripheral adiposity, and Aim 3 will uncover molecular signals and mechanisms for energy homeostasis.

摘要：代谢疾病的患者，例如肥胖，糖尿病和脂肪营养不良的患者 骨和脂肪质量，脂肪分布和能量稳态。这些涉及的基本机制 失调知之甚少。骨骼和脂肪组织都是内分泌器官，也是分泌因素 调节能量代谢。骨合成骨细胞和脂肪形成脂肪细胞是从中得出的 常见的间充质祖细胞。在 骨质疏松症，糖尿病和衰老。骨折风险最高的骨质疏松骨骼总是会增加 骨髓脂肪。这些临床观察结果表明，靶向骨髓脂肪可能是对这些的一种治疗方法 美国成年人的疾病和200万骨折，这些疾病是由于骨质疏松症和低骨骼质量而发生的。 但是，骨髓脂肪的起源和功能及其与骨骼和其他的关系 外围脂肪库不是很清楚。骨髓脂肪是一个独特的脂肪仓库，位于 骨头与白色或棕色脂肪组织不同。在这项研究中，我们旨在鉴定分子 具有骨骼和脂肪合并症的代谢疾病的基础机制，尤其是新因素 由成骨细胞和骨细胞分泌，可以调节骨髓成生成，外周脂肪分布， 能量稳态和成人骨骼的维持。 RUNX2转录因子对于在间充质祖细胞对细胞的细胞的承诺是必不可少的 骨骼谱系。由于成骨细胞的完全损失，Runx2基因的全球无效小鼠是胚胎致死的 分化和骨形成。我们最近发布了Runx2对于软骨细胞也是必不可少的 增殖，肥厚性成熟和内软骨骨化。我们的初步数据显示了选择性 成熟成骨细胞和骨细胞中RUNX2的缺乏抑制产后骨合成并触发快速 骨质疏松症，过早衰老和死亡的发作。 RUNX2活性抑制了间充质细胞的承诺 到脂肪细胞谱系。在成骨细胞/骨细胞中的runx2删除导致几乎没有内脏 肥胖，但骨髓成生成的急剧增加。我们进一步证明了runx2块 通过改变能量代谢和抑制胰岛素中AKT和ERK的临界信号传导来改变脂肪形成 途径。基于初步数据，我们假设Runx2从成熟成骨细胞调节信号 骨细胞控制骨髓脂肪形成，外周脂肪分布和能量稳态。我们将 利用新颖的小鼠模型来测试我们的假设三个特定目标。 AIM 1将检查Runx2的作用 成人脂肪和骨骼的相互维持中，缺乏成骨细胞和骨细胞。 AIM 2将测试 成骨细胞/成骨细胞对骨髓和周围肥胖的需求，AIM 3将发现分子 能量稳态的信号和机制。