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（由申请人提供）：锻炼可能是被认为可以预防骨质疏松症和肥胖症的单一“干预措施”，但机械信号抑制其发病机制的方式仍然未知。每日短暂的高频（30-90 Hz）、低幅度（<0.4g）机械信号（LMMS）对骨骼和肌肉都有合成代谢作用。令人意外的发现是，这些信号还抑制脂肪生成，接受 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 的截然不同的反应表明这些信号影响间充质干细胞 (MSC) 的分化途径。对于人类来说，这将有助于解释为什么久坐的生活方式会导致骨质疏松症和肥胖症这两种看似不同的疾病，并且可能表明 LMMS 通过定义 MSC 的命运来影响骨骼、肌肉或脂肪内的常驻细胞群，从而减少脂肪生成并增强肌肉骨骼系统。我们假设 LMMS 驱动 MSC 向骨骼和肌肉表型发展，同时抑制肥胖的途径。设计了三个具体目标，以更好地了解 LMMS 影响生长、衰老、肥胖和患病动物身体成分的方式： 1. 为了识别参与 LMMS 组织反应的基因，年轻雄性 B6 小鼠将每天接受 LMMS，并且骨髓、脂肪和骨骼中 96 个候选基因（代表参与调节这些组织的基因）从早期到晚期（4 天、6 周和 12 周）的表达水平将与 骨量和脂肪量的变化，并与基线和年龄匹配的对照进行比较。 2. LMMS 的长期表型影响及其影响饮食和肥胖遗传模型的能力，将在正常或高脂肪饮食（饮食诱导肥胖）的健康雄性 B6 小鼠以及易于肥胖的转基因小鼠品系（瘦素缺乏 ob/ob）中在 3 个月和 6 个月时确定。将量化骨髓、脂肪和骨骼的状态，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，并与对照进行比较。 3. 为确定 LMMS 是否影响 MSC 的分化途径，对接受 GFP+ 供体骨髓移植的受辐射 C57BL/6J 小鼠 (B6) 进行 LMMS，并在 6 周和 12 周后，将脂肪、骨髓和骨骼中 GFP+ 细胞的数量与年龄匹配的受体 GFP+ 对照进行比较。为了确定 MSC 是否可以独立地受到 LMMS 的影响，将使用用于传递 LMMS 的体外系统在 MSC 培养物 (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对其机械环境的微妙变化做出反应，并代表在建立抑制骨质疏松症和肥胖症的非药物方法方面迈出了一步。公共健康相关性：通过低强度应变增强骨小梁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。上一期资助的研究还表明，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来显着抑制肥胖，这表明了一种以前未被认识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临床作为控制骨质疏松症和肥胖症的安全、非药物干预措施奠定基础。