Endosteal Adipose in Age-Associated Osteopenia

年龄相关性骨量减少/骨质疏松症(老年性或II型)的发生是因为 与骨吸收相关的骨形成，导致骨的净损失。与之相关联的是， 骨内腔内脂肪的数量。在人类和动物模型上的大量研究表明， 骨髓脂肪和骨形成之间有很强的负相关关系。我们的中心假设是 骨髓脂肪的发展导致骨形成减少。我们的使命是双重的；第一， 确凿地证明，骨髓脂肪细胞的发育对骨形成有有害影响，以及 第二，了解脂肪细胞调节成骨细胞抑制的机制。鉴于……的复杂性 骨内隔、全身因素的影响以及成骨细胞和成骨细胞的共同前体 脂肪细胞，这是一个棘手的问题，需要真正独特的调查方法。四种可能 假说可以解释骨髓脂肪细胞如何影响骨形成。第一，骨髓的辨证 间充质干细胞(MSC)向脂肪细胞的分化可能限制成骨细胞的分化(H1：分化转变)。 其次，脂肪发育可能会耗尽可用的成骨干细胞(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，脂肪细胞可影响新的成骨细胞的发育或活性(H4：接触 抑制)。我们建议的一个独特方面是，我们不是专注于单一的假设，而是将 使用10种不同的基因敲除和转基因小鼠来解决这四个问题。这些型号的MSC将用于 一种独特的同位成骨模型，即前体细胞被植入宿主小鼠体内形成 有完整脂肪骨髓腔的骨小骨。我们提出了三个具体的目标：(1)检查骨骼 增加或减少脂肪细胞分化的模型的形成，(2)检查骨骼 在脂肪可通过靶向凋亡调节的模型中的形成，以及(3)检查 瘦素、脂联素或PPAR-γ激动剂的旁分泌信号。如果成功，我们的研究将证明 脂肪细胞是否真的影响成骨细胞的发育或功能，我们将进一步证明 脂肪调节机制(S)。了解脂肪细胞在调节骨形成中的功能是 最重要的是开发新的治疗方法来解决与年龄相关的骨丢失。

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.