Inflammation and bone loss with aging

描述（由申请人提供）：衰老伴随免疫功能下降、骨量丢失和骨髓脂肪积累。过氧化物酶体增殖物激活受体-γ（过氧化物酶体增殖物激活受体-γ，过氧化物酶体增殖物激活受体-γ）是调节脂肪和骨细胞形成的关键因子。研究表明，PPARγ不足可增加骨量，这表明靶向PPARγ可能是新的抗骨质疏松治疗的新策略。然而，目前尚不清楚PPARγ不足如何增加骨质，因为脂肪组织中PPARγ基因的缺失也会增加骨量，而脂肪的全面减少会导致严重的糖尿病和胰岛素抵抗。我们假设，骨特异性的PPARγ失活（仅阻断骨髓脂肪形成）将消除骨髓脂肪产生的炎症反应，包括炎性细胞因子和炎性细胞，增加成骨细胞的可用性和活性，并改善免疫功能，从而降低衰老中骨丢失的速度。这一假说的基础是骨髓脂肪随着年龄的增长而增加，脂肪组织产生大量的炎性细胞因子。除了抑制骨细胞发育外，预计这些细胞因子会降解骨髓微环境（引起慢性炎症）并抑制造血作用，导致祖细胞从主要淋巴细胞比例转变为骨髓细胞比例（造血作用偏斜），因为骨髓是免疫系统起源的地方。我们将使用两种PPARγ基因敲除小鼠模型来验证我们的假设，一种仅阻断骨髓脂肪细胞形成，另一种减少全身脂肪量。提出了两个具体目标。目的1将检验特定假设，即PPARγ控制成人骨稳态，但不控制骨骼发育或生长，目的2将检验特定假设，即PPARγ的失活消除脂肪产生的炎症反应，包括细胞因子和炎症细胞，并增强免疫功能，免疫功能随衰老而下降，可能导致年龄诱导的骨质流失。这项研究的结果将为我们目前对PPARγ调节骨代谢的机制的理解提供新的线索，并有助于开发新的抗骨质疏松症疗法。

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 (PPARγ) is a key factor regulating fat and bone cell formation. Studies show that PPARγ insufficiency can increase bone mass, suggesting that targeting PPARγ could be a novel strategy for new anti-osteoporosis therapies. However, it is not clear how PPARγ insufficiency increases bone because deletion of PPARγ 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 PPARγ 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 PPARγ 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 PPARγ controls adult bone homeostasis but not skeletal development or growth, and Aim 2 will test the specific hypothesis that inactivation of PPARγ 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 PPARγ regulates bone metabolism and help develop new anti-osteoporosis therapies.