Myeloid precursors and the microbiome in the osteoimmunology of aging

描述(由申请人提供)：在过去的十年里，骨骼细胞和免疫系统之间的密切关系受到了重视。这一新领域被称为“骨免疫学”。免疫细胞、成骨细胞(OB)和骨吸收破骨细胞(OC)之间的关系失调会导致骨质疏松症、骨肿瘤和关节炎等疾病。尽管这些情况在老年人中普遍发生，但对老年动物的骨免疫学研究还不够深入。随着全球人口老龄化，这些问题将变得更加普遍，这种知识匮乏所造成的临床和社会影响将变得更加重要。这笔赠款旨在通过利用最近发展的OC生物学模型和一个令人兴奋的观察结果，即无菌(GF)小鼠受到保护，免受与年龄相关的骨质疏松症的影响，从而更好地了解衰老如何影响骨免疫学。OCs在细胞因子RANKL的影响下分化为髓系前体细胞，RANKL来源于骨细胞、激活的T细胞或细胞因子刺激的基质细胞。在骨质疏松、关节炎和骨恶性肿瘤中观察到的骨骼异常是过度活跃的OCS的基础。多年来，破骨细胞前体(OCP)的身份一直没有明确的定义。最近，我们发现OCP包括少量的CD11blowLy6chigh髓系细胞。有趣的是，这些OCP还展示了令人惊讶的第二个功能：它们能够在体外和体内炎症性关节炎的背景下有效地抑制T细胞反应。这笔赠款的前两个目的是评估一种假说，即CD11blowLy6chigh OCP的年龄相关变化是两种普遍的衰老现象的基础：骨丢失和细胞免疫功能降低。最终目标是在我们最近对微生物群如何影响免疫系统和新陈代谢导致疾病的集体理解发生爆炸之后出现的。然而，人们对微生物区系如何影响骨生物学知之甚少。在与北卡罗来纳大学国家灵生啮齿动物资源中心的巴尔弗·萨托博士的合作下，我们产生了初步数据，表明微生物组是年龄相关性骨质疏松症的决定因素。这笔赠款的目的3将确定在老年小鼠中操纵微生物组如何改变骨量，以及来自老年小鼠的微生物组是否能够导致年轻动物的骨质疏松。这项建议的优势包括它解决的重大问题(与年龄相关的骨骼质量和免疫力下降)，拥有OC生物学、免疫学和微生物组专业知识的不同研究团队，应用最先进的小鼠骨免疫学模型，以及关于衰老对OCP生物学和微生物组相关骨丢失的影响的创新假设。这些研究将进一步加深我们对衰老如何影响骨生物学和免疫交叉的理解，并可能导致治疗骨质疏松症、关节炎、癌症和感染的新策略。

DESCRIPTION (provided by applicant): Over the last decade, an intimate relationship between cells of the skeletal and immune systems has come under appreciation. This new field has been termed "osteoimmunology". A disturbance in the relationship between immune cells, bone forming osteoblasts (OB) and bone resorbing osteoclasts (OC) results in diseases such as osteoporosis, bone tumors and arthritis. Despite the common occurrence of these conditions in the elderly, osteoimmunology in aged animals has been understudied. As the worldwide population ages, these problems will become more common and the clinical and social implications created by this dearth of knowledge will grow in significance. This grant seeks to establish a better understanding of how aging affects osteoimmunology by leveraging recently developed models of OC biology and an exciting observation that germ-free (GF) mice are protected from age related osteoporosis. OCs differentiate from myeloid precursors under the influence of the cytokine RANKL, derived from osteocytes, activated T-cells or cytokine stimulated stromal cells. Overactive OCs underlie the skeletal abnormalities observed in osteoporosis, arthritis and bone malignancy. For years, the identity of the osteoclast precursor (OCP) was poorly defined. Recently, we showed that OCPs comprise a minor population of CD11blowLy6chigh myeloid cells. Interestingly, these OCPs exhibit a surprising second function: they are capable of potently suppressing T cell responses in vitro and in the setting of inflammatory arthritis in vivo. The first two aims of this grant evaluate the hypothesis that age related changes in CD11blowLy6chigh OCPs underpin two universal phenomena of aging: bone loss and reduced cellular immunity. The final aim comes on the heels of a recent explosion in our collective understanding of how the microbiome influences the immune system and metabolism to cause disease. However, relatively little is known about how the microbiota influences bone biology. In collaboration with Dr. Balfour Sartor at the National Gnotobiotic Rodent Resource Center at UNC we have generated preliminary data suggesting that the microbiome is a determinant of age-related osteoporosis. Aim 3 of this grant will determine how manipulation of the microbiome in aged mice changes bone mass and whether the microbiome from aged mice is capable of inducing osteoporosis in young animals. Strengths of this proposal include the significant problem it addresses (age related declines in bone quality and immunity), the diverse team of investigators with expertise in OC biology, immunology and the microbiome, the application of state of the art mouse models of osteoimmunology and innovative hypotheses regarding the effect of senescence on OCP biology and microbiome associated bone loss. These studies will further our understanding of how aging affects the intersection of bone biology and immunity, and may lead to new treatment strategies for osteoporosis, arthritis, cancer and infection.