Inflammation and bone loss with aging

描述（由申请人提供）：衰老伴随着免疫功能下降、骨量减少和骨髓脂肪积累。过氧化物酶体增殖激活受体（PPAR?）是调节脂肪和骨细胞形成的关键因子。研究表明PPAR？不足可以增加骨量，提示靶向PPAR？可能是一种新的抗骨质疏松疗法的新策略。然而，目前尚不清楚PPAR如何？PPAR缺失导致骨质增加？脂肪组织中的基因也会增加骨量，而脂肪的整体减少会导致严重的糖尿病和胰岛素抵抗。我们假设骨特异性PPAR？失活，只阻断骨髓脂肪的形成，将消除骨髓脂肪产生的炎症反应，包括炎症细胞因子和炎症细胞，增加成骨细胞的可用性和活性，提高免疫功能，从而减少衰老过程中骨质流失的速度。这一假设是基于骨髓脂肪随着年龄的增长而增加，脂肪组织产生大量的炎症细胞因子。除了抑制骨细胞发育外，这些细胞因子还会降解骨髓微环境（引起慢性炎症）并抑制造血功能，导致祖细胞从主要淋巴细胞向髓细胞的转变（造血功能失调），因为骨髓是免疫系统的起源。我们将使用两个PPAR？敲除小鼠模型，一个只阻断骨髓脂肪细胞的形成，另一个减少全身脂肪量。提出了两个具体目标。目标1将检验PPAR？控制成人骨稳态，但不控制骨骼发育或生长，Aim 2将测试PPAR失活的特定假设？消除脂肪产生的炎症反应，包括细胞因子和炎症细胞，增强免疫功能，免疫功能随着年龄的增长而下降，可能导致年龄引起的骨质流失。这项研究的结果将为我们目前对PPAR？调节骨代谢，帮助开发新的抗骨质疏松疗法。

DESCRIPTION (provided by applicant): Aging is coupled with a decline of immune function, loss of bone mass and accumulation of marrow fat. Peroxisome proliferator-activated receptor-gamma (PPAR?) is a key factor regulating fat and bone cell formation. Studies show that PPAR? insufficiency can increase bone mass, suggesting that targeting PPAR? could be a novel strategy for new anti-osteoporosis therapies. However, it is not clear how PPAR? insufficiency increases bone because deletion of PPAR? gene in fat tissue also increases bone mass, and that global reduction of fat causes severe diabetes and insulin resistance. We hypothesize that bone-specific PPAR? inactivation, which blocks only bone marrow fat formation, will eliminate marrow fat-generated inflammatory responses, including inflammatory cytokines and inflammatory cells, increases the availability and activity of osteoblasts, and improves immune function, thereby reducing the pace of bone loss in aging. This hypothesis is formulated on the basis that marrow fat increases with aging and fat tissue produces large quantities of inflammatory cytokines. In addition to inhibit bone cell development, these cytokines are predicted to degrading the bone marrow microenvironment (causing chronic inflammation) and inhibiting the hematopoiesis resulting in a shift of progenitor cell from a predominant lymphoid to a myeloid proportion (skewing of hematopoiesis) because bone marrow is the place where immune system is originated. We will test our hypothesis using two PPAR? knockout mouse models, one blocks only bone marrow fat cell formation and the other reduces whole body fat mass. Two specific aims are proposed. Aims 1 will test the specific hypothesis that PPAR? controls adult bone homeostasis but not skeletal development or growth, and Aim 2 will test the specific hypothesis that inactivation of PPAR? eliminates fat-generated inflammatory responses, including cytokines and inflammatory cells, and boosts the immune function, which declines with aging and may contribute to age-induced bone loss. Results of this research will shed new light on our current understanding of the mechanisms by which PPAR? regulates bone metabolism and help develop new anti-osteoporosis therapies.