Bone loss with aging occurs due to increased PPAR-g activity in marrow stem cells

骨髓干细胞中 PPAR-g 活性增加导致骨质随衰老而流失

• 批准号: 7152348
• 负责人: Beata Anna Lecka-Czernik
• 金额: $ 29.77万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2007-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152348
• 关键词: adipocytes; age difference; aging; biological signal transduction; bone marrow; cell differentiation; computed axial tomography; gene induction /repression; genetic regulation; hematopoietic stem cells; histology; inhibitor /antagonist; laboratory mouse; microarray technology; morphometry; osteoblasts; osteogenesis; osteoporosis; peroxisome proliferator activated receptor; phenylamide; polymerase chain reaction; rosiglitazone; stem cell transplantation

DESCRIPTION (provided by applicant): Bone loss with aging results from attenuated and unbalanced bone turnover, and is associated with a decreased number of bone-forming osteoblasts, increased number of bone-resorbing osteoclasts, and increased number of fat cells, adipocytes, in the bone marrow. Osteoblasts and adipocytes originate from marrow-derived mesenchymal stroma/stem cells (MSCs). The milieu of intracellular and extracellular signals controls MSC lineage allocation. Emerging evidence indicates that the adipocyte-specific transcription factor peroxisome proliferator- activated receptor-gamma (PPARg) acts as a positive regulator of marrow adipocyte formation and negative regulator of osteoblast development. In vivo, increased activity of PPARg leads to bone loss, similar to bone loss with aging, whereas its decreased activity results in increased bone mass. The pro-adipocytic and the anti- osteoblastic properties of PPARg are determined by the type of ligand and can be distinguished, suggesting separate mechanisms by which PPARg controls bone mass and fat mass in bone. During aging, the status of MSCs changes with respect to both their intrinsic differentiation potential and production of signaling molecules that contribute to the formation of a specific marrow micro-environment. The expression of PPARg and production of its natural activators (e.g., oxidized fatty acids) increases, suggesting increased activity of this nuclear receptor. Increased activity of PPARg down-regulates the expression and activity of multiple regulatory pathways, including Wnt, TGF-beta, and IGF-1, suggesting the role of this transcription factor in the regulation of the extrinsic signaling milieu. We propose that age-related bone loss results from the increased anti-osteoblastic activity of PPARg, which results in both intrinsic changes in the differentiation of MSCs and a decrease in pro-osteoblastic signaling in the marrow micro-environment. The following Specific Aims will test this hypothesis: Aim 1: Determine regulatory mechanisms by which PPARg suppresses osteoblast differentiation during aging. Aim 2: Determine the effects of PPAR-g controlled intracellular mechanisms and microenvironmental changes on bone formation with the model of distraction osteogenesis (DO). An understanding of the effects of aging on the interrelationship between MSC differentiation potential and the modulatory effects of the bone marrow environment on this process is the starting point for the development of successful therapies for osteoporosis that will specifically target bone and bone marrow stem cells. Completion of the above aims should enable us to determine the role of PPARg in this process and will allow designing therapeutic interventions that will selectively block PPARg anti-osteoblastic activity.

描述（由申请人提供）：骨质流失导致骨骼衰减和不平衡的骨骼更新，与骨形成骨成骨细胞的数量减少，骨头莫罗的脂肪细胞数量增加，脂肪细胞数量增加，脂肪细胞的数量增加。成骨细胞和脂肪细胞起源于骨髓衍生的间充质基质/干细胞（MSC）。细胞内和细胞外信号的环境控制MSC谱系分配。新兴证据表明，脂肪细胞特异性转录因子过氧化物组增殖物激活的受体伽马（PPARG）充当骨髓脂肪细胞形成的阳性调节剂和成骨细胞发育的阴性调节剂。在体内，PPARG的活性增加会导致骨质流失，类似于衰老的骨质流失，而其活性降低会导致骨骼质量增加。 PPARG的促脂肪细胞和抗成骨细胞特性由配体的类型确定，可以区分，这表明PPARG控制骨骼中的骨骼质量和脂肪质量。在衰老期间，MSC的状态在其内在分化潜力和信号分子的产生都会发生变化，这有助于形成特定的骨髓微环境。 PPARG的表达和其天然激活剂的产生（例如，氧化脂肪酸）增加，表明该核受体的活性增加。 PPARG的活性增加下调了包括Wnt，TGF-beta和IGF-1在内的多种调节途径的表达和活性，这表明该转录因子在调节外部信号环境中的作用。我们提出，与年龄相关的骨质流失是由于PPARG的抗肌细胞活性增加而导致的，这既导致MSC分化的内在变化，又导致骨髓微环境中的促骨细胞信号传导降低。以下特定目的将检验以下假设：目标1：确定PPARG在衰老过程中抑制成骨细胞分化的调节机制。 AIM 2：通过分散注意力的骨化模型（DO），确定PPAR控制的细胞内机制和微环境变化对骨形成的影响。了解衰老对MSC分化潜力与骨髓环境对该过程的调节作用之间相互关系的影响的理解是开发成功骨质疏松症的成功疗法的起点，骨质疏松症将专门针对骨髓和骨髓干细胞。上述目标的完成应使我们能够确定PPARG在此过程中的作用，并允许设计治疗干预措施，以选择性地阻止PPARG抗肌细胞活动。