Endosteal Adipose in Age-Associated Osteopenia

年龄相关性骨质减少中的骨内脂肪

• 批准号: 7149432
• 负责人: Kurt David Hankenson
• 金额: $ 34.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149432
• 关键词: adipocytes; aging; bone; fats; model; osteoblasts; osteogenesis; osteopenia

DESCRIPTION (provided by applicant): Age-associated osteopenia/osteoporosis (Senile or Type II) develops because there is a decrease in bone formation relative to resorption resulting in net loss of bone. In association there is an increase in the amount of adipose in the endosteal cavity. Numerous studies in humans and animal models have shown that there is a strong inverse correlation between marrow fat and bone formation. Our central hypothesis is that the development of marrow fat results in decreased bone formation. Our mission is two-fold; first, to definitively prove that the development of marrow adipocytes has a deleterious effect on bone formation, and second, to understand the mechanism of adipocyte-regulated osteoblast inhibition. Given the complexities of the endosteal compartment, the influence of systemic factors, and the shared precursors of osteoblasts and adipocytes, this is an intractable problem that requires a truly unique investigative approach. Four possible hypotheses may explain how marrow adipocytes affect bone formation. First, the differentiation of marrow mesenchymal stem cells (MSC) to adipocytes may limit osteoblast differentiation (H1: Differentiation shift). Second, adipose development may deplete the pool of available osteoblast stem cells (H2: MSC depletion). Third, adipocytes could secrete factors that regulate bone formation (H3: Paracrine effect). Fourth, through contact inhibition, adipocytes could affect the development or activity of new osteoblasts (H4: Contact inhibition). A unique aspect of our proposal is that we are not focused on a single hypothesis, but will address all four using ten different knockout and transgenic mice. MSC from these models will be used in a unique model of appositional bone formation whereby precursors cells are implanted in host mice to form a bone ossicle with an intact fatty-marrow cavity. We propose three specific aims: (1) To examine bone formation in models that have either increased or decreased adipocyte differentiation, (2) To examine bone formation in a model where fat can be regulated through targeted apoptosis, and (3) To examine the role of paracrine signaling by leptin, adiponectin, or PPAR-gamma agonists. If successful our study will demonstrate whether adipocytes truly impact osteoblast development or function, and further, we will demonstrate the mechanism(s) of adipo-regulation. Understanding the function of adipocytes in regulating bone formation is paramount for developing new therapies to address age-associated bone loss.

描述（由申请人提供）：与年龄相关的骨质减少症/骨质疏松症（老年或II型）出现，因为相对于吸收，骨形成降低，导致骨骼净损失。在相关的情况下，内骨腔中的脂肪量增加。在人类和动物模型中进行了许多研究表明，骨髓脂肪和骨形成之间存在很强的逆相关性。我们的中心假设是骨髓脂肪的发展导致骨形成减少。我们的任务是两个方面；首先，确定证明骨髓脂肪细胞的发展对骨形成具有有害作用，其次是了解脂肪细胞调节的成骨细胞抑制的机理。鉴于内沟腔室的复杂性，系统因素的影响以及成骨细胞和脂肪细胞的共同前体，这是一个棘手的问题，需要一种真正独特的研究方法。四个可能的假设可以解释骨髓脂肪细胞如何影响骨形成。首先，骨髓间充质干细胞（MSC）与脂肪细胞的分化可能会限制成骨细胞分化（H1：分化移位）。其次，脂肪发育可能会耗尽可用成骨细胞干细胞的池（H2：MSC耗竭）。第三，脂肪细胞可以分泌调节骨形成的因素（H3：旁分泌效应）。第四，通过接触抑制，脂肪细胞可能会影响新成骨细胞的发育或活性（H4：接触抑制）。提案的一个独特方面是，我们不专注于一个假设，而是使用十个不同的敲除和转基因小鼠来解决所有四个假设。这些模型的MSC将用于唯一的同骨骨形成模型，从而将前体细胞植入宿主小鼠中，以形成具有完整的脂肪 - 龙腔的骨耳。我们提出了三个具体目的：（1）检查在脂肪细胞分化增加或减少的模型中的骨形成，（2）在模型中检查骨形成，在该模型中，可以通过靶向凋亡来调节脂肪，以及（3）检查通过瘦素，脂肪素，脂肪蛋白或PPAR-GAMMA或PPAR-GAMMA AGONIST的旁分泌信号传导的作用。如果成功，我们的研究将证明脂肪细胞是否真正影响成骨细胞的发展或功能，此外，我们将证明脂肪调节的机制。了解脂肪细胞在调节骨形成中的功能对于开发新疗法以解决与年龄相关的骨质流失至关重要。