Augmentation of Trabecular Bone by Low Magnitude Strain

通过低强度应变增强骨小梁

• 批准号: 7582929
• 负责人: CLINTON T RUBIN
• 金额: $ 35.71万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582929
• 关键词: Adipocytes; Adipose tissue; Adolescence; Age; Aging; Alkaline Phosphatase; Animals; Biological Assay; Body Composition; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Bone Tissue; Candidate Disease Gene; Cell Differentiation process; Cell Line; Cells; Cerebral Palsy; Child; Clinic; Condition; Daily; Diabetes Mellitus; Diet; Disease; Elderly; Environment; Exercise; Fatty acid glycerol esters; Female; Femur; Flow Cytometry; Foundations; Frequencies; Funding; Genes; Genetic Models; Glucose tolerance test; Green Fluorescent Proteins; Health; Human; In Vitro; Incidence; Intervention; Label; Left; Leptin; Life Style; Liver; Marrow; Measurement; Measures; Mechanics; Mesenchymal Stem Cells; Metabolic; Metabolism; Modeling; Mouse Strains; Mus; Muscle; Musculoskeletal; Musculoskeletal System; Nonesterified Fatty Acids; Numbers; Obesity; Osteogenesis; Osteoporosis; Ovariectomy; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Process; Production; Protocols documentation; Public Health; RNA; Range; Rate; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Serum; Signal Transduction; Stem cells; System; Time; Tissues; Transgenic Organisms; Translating; Transplantation; Triglycerides; Visceral; Work; abdominal fat; base; bone; bone loss; day; design; feeding; immunocytochemistry; improved; in vivo; intraperitoneal; lipid biosynthesis; male; mineralization; oil red O; respiratory; response; sedentary; subcutaneous; substantia spongiosa; tibia; young adult

DESCRIPTION (provided by applicant): Exercise is perhaps the single "intervention" recognized as a deterrent to both osteoporosis and obesity, yet the manner in which mechanical signals inhibit their pathogenesis remains unknown. Brief daily periods of high frequency (30-90 Hz), low magnitude (<0.4g) mechanical signals (LMMS) are anabolic to both bone and muscle. In an unexpected finding, these signals also suppress adipogenesis, with 29% less total visceral abdominal fat in mice subject to 12w of LMMS. The starkly distinct response of these tissues (?bone & muscle; ?fat) to LMMS suggests that these signals influence the differentiation pathway of mesenchymal stem cells (MSCs). Translated to the human, this would help explain why a sedentary lifestyle is permissive to both osteoporosis and obesity, seemingly distinct diseases, and could suggest that LMMS reduce adipogenesis and strengthen the musculoskeletal system as much by defining the fate of MSCs as influencing the resident cell population within bone, muscle, or fat. We hypothesize that LMMS drive MSCs towards a bone and muscle phenotype, simultaneously suppressing a path towards adiposity. Three specific aims are designed to better understand the means by which LMMS influences the body composition of the growing, aging, obese and diseased animal: 1. To identify those genes involved in the tissue response to LMMS, young male B6 mice will be subject to daily LMMS, and early through late (4d, 6 & 12w) expression levels of 96 candidate genes in marrow, fat and bone, representing those involved in regulating these tissues, will be correlated to alterations in bone and fat mass, and compared to baseline and age matched control. 2. The long-term phenotypic impact of LMMS, and their ability to influence dietary and genetic models of obesity, will be defined at 3 & 6 months in healthy male B6 mice fed a normal or high-fat diet (Diet Induced Obesity), as well as a transgenic strain of mice prone to adiposity (leptin-deficient ob/ob). The status of marrow, fat and bone, and level of triglycerides and free fatty acid in the serum, liver, muscle and adipose tissue, will be quantified and compared to controls. 3. To determine if LMMS influences the differentiation pathway of MSCs, irradiated C57BL/6J mice (B6) transplanted with marrow from GFP+ donors will be subject to LMMS, and following 6 & 12w, the number of GFP+ cells in fat, marrow and bone will be compared to age matched recipient GFP+ controls. To establish if MSCs can be independently influenced by LMMS, the ability of these signals to suppress adipogenesis and promote osteoblastogenesis will be evaluated in MSC cultures (C3H10T1/2) using an in vitro system used to deliver LMMS. Together, these studies will help define how the musculoskeletal, adipose and stem cell systems respond to subtle changes in their mechanical environment, and represents a step in establishing a non-drug means of inhibiting osteoporosis and obesity. PUBLIC HEALTH RELEVANCE: Augmentation of Trabecular Bone by Low Magnitude Strain This work will investigate the mechanisms behind the anabolic potential of extremely low- magnitude mechanical signals, and how they strengthen both bone and muscle. Research over the last period of funding has also shown that these signals markedly suppress adiposity, by influencing the differentiation pathway of mesenchymal stem cells rather than elevating the animal's metabolism, indicating a previously unrecognized mechanical means of the regulating fat and bone production. This research will provide the foundation to translate this work to the clinic as a safe, non-pharmacologic, intervention for the control of osteoporosis and obesity.

描述(申请人提供)：运动可能是公认的对骨质疏松症和肥胖症都有威慑作用的单一“干预”，但机械信号抑制其发病机制的方式仍不清楚。每天短暂的高频(30-90赫兹)、低强度(0.4克)机械信号(LMM)对骨骼和肌肉都是合成代谢的。在一项意想不到的发现中，这些信号还抑制了脂肪生成，服用12周LMMs的小鼠内脏腹部脂肪总量减少了29%。这些组织(骨骼和肌肉；脂肪)对LMMs的明显反应表明，这些信号影响了间充质干细胞(MSCs)的分化途径。翻译到人类身上，这将有助于解释为什么久坐的生活方式对骨质疏松和肥胖这两种看似不同的疾病都是允许的，并可能表明LMM通过定义MSCs的命运影响骨、肌肉或脂肪中的常驻细胞群，从而减少脂肪生成并加强肌肉骨骼系统。我们假设LMM驱动MSCs朝向骨骼和肌肉的表型，同时抑制肥胖的途径。为了更好地理解LMM对生长、衰老、肥胖和疾病动物的身体组成的影响，我们设计了三个特定的目标：1.为了确定那些与LMM的组织反应有关的基因，年轻的雄性B6小鼠将受到每天的LMM的影响，在骨髓、脂肪和骨骼中的96个候选基因的早期到晚期(4d、6和12w)的表达水平将与骨和脂肪质量的变化相关，并与基线和年龄匹配的对照组进行比较。2.LMM的长期表型影响，以及它们影响肥胖饮食和遗传模型的能力，将在3-6个月后在喂食正常或高脂饮食(饮食诱导肥胖)的健康雄性B6小鼠以及容易肥胖的转基因小鼠(瘦素缺乏ob/ob)中确定。骨髓、脂肪和骨骼的状况，以及血清、肝脏、肌肉和脂肪组织中甘油三酯和游离脂肪酸的水平将被量化，并与对照组进行比较。3.为了确定骨髓基质细胞是否影响骨髓间充质干细胞的分化途径，将GFP+供者骨髓移植到照射后的C57BL/6J小鼠(B6)，6~12周后，将脂肪、骨髓和骨骼中的GFP+细胞数量与年龄匹配的受体GFP+细胞对照进行比较。为了确定骨髓间充质干细胞是否可以独立地受到LMM的影响，我们将使用一种用于输送LMM的体外系统，在MSC培养(C3H10T1/2)中评估这些信号抑制脂肪生成和促进成骨细胞生成的能力。总之，这些研究将有助于确定肌肉骨骼、脂肪和干细胞系统如何应对机械环境中的细微变化，并代表着在建立抑制骨质疏松症和肥胖的非药物手段方面迈出的一步。公共卫生相关性：低强度应变增强松质骨这项工作将研究极低强度机械信号的合成代谢潜力背后的机制，以及它们如何增强骨骼和肌肉。过去一段时间的研究还表明，这些信号通过影响间充质干细胞的分化途径而不是提高动物的新陈代谢，显著抑制肥胖，这表明了一种以前未知的调节脂肪和骨产生的机械手段。这项研究将为将这项工作转化为一种安全的、非药物的、控制骨质疏松症和肥胖的干预措施应用于临床提供基础。