Augmentation of Trabecular Bone by Low Magnitude Strain

通过低强度应变增强骨小梁

• 批准号: 7688652
• 负责人: CLINTON T RUBIN
• 金额: $ 34.53万
• 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/7688652
• 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 Culture Techniques; Cell Line; Cells; Cerebral Palsy; Child; Clinic; Diabetes Mellitus; Diet; Disease; Elderly; Environment; Exercise; Fatty acid glycerol esters; Female; Femur; Flow Cytometry; Foundations; Frequencies; Funding; Genes; Genetic Models; Glucose tolerance test; 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; Obesity; Osteogenesis; Osteoporosis; Ovariectomy; Pathogenesis; Pathway interactions; Phenotype; Population; Predisposition; Process; Production; Protocols documentation; RNA; 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; design; feeding; immunocytochemistry; improved; in vivo; intraperitoneal; lipid biosynthesis; male; mineralization; non-drug; oil red O; osteogenic; public health relevance; respiratory; response; sedentary; stem cell differentiation; stem cell population; 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（由申请人提供）：运动可能是对骨质疏松症和肥胖症的威慑作用的单一“干预”，但是机械信号抑制其发病机理的方式仍然未知。高频（30-90 Hz），低幅度（<0.4G）机械信号（LMM）的短期每日期间都是骨骼和肌肉的代谢。在一个意外的发现中，这些信号也抑制了脂肪形成，在12W LMM的小鼠中，总内脏腹部脂肪减少了29％。这些组织（？骨和肌肉；？脂肪）对LMM的明显不同的反应表明，这些信号会影响间充质干细胞（MSC）的分化途径。翻译成人类，这将有助于解释为什么久坐的生活方式允许骨质疏松和肥胖，看似鲜明的疾病，并且可以表明LMMS通过将MSC的命运定义为骨骼，骨骼，肌肉，肌肉，肌肉或脂肪，从而将肌肉骨骼系统降低并增强肌肉骨骼系统。我们假设LMM将MSC驱动到骨骼和肌肉表型，同时抑制了通往肥胖的路径。 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骨骼和脂肪质量的改变，并与基线和年龄匹配的对照相比。 2。LMM的长期表型影响及其影响肥胖的饮食和遗传模型的能力，将在健康的雄性B6小鼠中定义为3和6个月的正常或高脂饮食（饮食诱导的肥胖），以及容易发生脂肪的小鼠（脂肪蛋白）的转基因菌株（瘦素缺乏的肥胖ob/ob）。骨髓，脂肪和骨骼的状态以及甘油三酸酯的水平以及血清，肝脏，肌肉和脂肪组织中的游离脂肪酸的状态将被定量并与对照组进行量化。 3。为了确定LMM是否影响MSC的分化途径，用GFP+供体移植的MRROW受辐照的C57BL/6J小鼠（B6）将受到LMM的约束，然后随后6＆12W，脂肪，骨髓和骨骼中的GFP+细胞数量将与年龄匹配的受体GFP+对照组比较。为了确定MSC是否可以受到LMM的独立影响，这些信号抑制掺杂和促进成骨细胞生成的能力将在MSC培养物（C3H10T1/2）中评估，并使用用于提供LMM的体外系统。这些研究共同有助于定义肌肉骨骼，脂肪和干细胞系统如何应对其机械环境的细微变化，并代表建立非药物抑制骨质疏松症和肥胖的方法。公共卫生相关性：小梁骨通过低幅度菌株增强，这项工作将调查极低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。在最后一段时期的研究还表明，这些信号通过影响间充质干细胞的分化途径而不是提升动物的代谢，从而显着抑制了肥胖，这表明先前未认识到的调节脂肪和骨骼产生的机械手段。这项研究将为将这项工作转化为诊所的基础，作为一种安全的，非药物的干预，以控制骨质疏松和肥胖。