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/骨质疏松症（老年性或II型）的发生是因为骨形成相对于骨吸收减少，导致骨净损失。与之相关的是骨内腔中脂肪量的增加。对人类和动物模型的大量研究表明，骨髓脂肪和骨形成之间存在很强的负相关性。我们的中心假设是骨髓脂肪的发育导致骨形成减少。我们的使命有两个：首先，明确证明骨髓脂肪细胞的发育对骨形成具有有害影响；其次，了解脂肪细胞调节的成骨细胞抑制的机制。考虑到骨内膜室的复杂性、全身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，需要真正独特的研究方法。四种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）向脂肪细胞的分化可能会限制成骨细胞分化（H1：分化转变）。其次，脂肪发育可能会耗尽可用的成骨细胞干细胞库（H2：MSC 耗尽）。第三，脂肪细胞可以分泌调节骨形成的因子（H3：旁分泌效应）。第四，通过接触抑制，脂肪细胞可以影响新成骨细胞的发育或活性（H4：接触抑制）。我们提案的一个独特之处在于，我们并不关注单一假设，而是使用十种不同的基因敲除和转基因小鼠来解决所有四个假设。来自这些模型的间充质干细胞将用于独特的同位骨形成模型，其中前体细胞被植入宿主小鼠体内，形成具有完整脂肪骨髓腔的骨小骨。我们提出了三个具体目标：（1）检查脂肪细胞分化增加或减少的模型中的骨形成，（2）检查可以通过靶向细胞凋亡调节脂肪的模型中的骨形成，以及（3）检查瘦素、脂联素或PPAR-γ激动剂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育或功能，并且进一步，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解决与年龄相关的骨质流失的新疗法至关重要。