Environmental PPAR Agonists Accelerate Aging of Bone and Impair Lymphopoiesis

描述(申请人提供)：越来越多的环境污染物被认为有能力激活脂肪细胞分化的主要调节因子--过氧化体增殖物激活受体(PPAR())，包括邻苯二甲酸酯和有机锡。由于用作防污剂，三丁基锡(TBT)一直是海洋环境中令人关注的污染物；然而，三丁基锡在农业杀虫剂、木材防腐剂和塑料制造中的使用导致了这种污染物的大量陆源来源，以至于在房屋灰尘中甚至可以检测到有机锡。我们的数据表明，TBT是骨髓基质细胞中PPAR的高效激活剂。脂肪细胞分化的EC50为~10 NM，该浓度在人体肝脏和血液中有机锡的测量范围内(0.1-500 NM)。骨髓是一种多功能器官，支持骨形成和淋巴生成，这两种功能在衰老过程中都会受到影响。单个间充质干细胞前体细胞同时产生脂肪细胞和成骨细胞，导致脂肪细胞和成骨细胞分化之间的相互关系。随着哺乳动物年龄的增长，骨髓中的脂肪量增加，伴随而来的是成骨细胞的丧失。此外，暴露于治疗II型糖尿病的治疗性PPAR3激活剂会导致患者脂肪骨形成，并增加骨折的风险。最近的文献表明，1)成骨细胞是最佳的淋巴生成所必需的，2)脂肪细胞是淋巴生成的负调控细胞。骨髓中的基质元素和B细胞前体的复杂平衡是维持B细胞终生发育所必需的，这对衰老的哺乳动物来说尤其关键，因为在衰老的哺乳动物中，骨髓中脂肪的积累与淋巴细胞生成的衰老是同时发生的。因此，我们假设，污染物驱动的PPAR(和脂肪细胞分化)的激活将导致骨骼的过早衰老，而脂肪细胞在骨髓中的积累和成骨细胞分化的抑制会导致丧失产生淋巴细胞的能力，以及骨骼完整性的丧失。为了验证这一假说，我们设计了以下特定目标：1.确定环境和治疗性PPAR(/RXR1)激动剂改变骨髓间充质干细胞分化的分子机制。2.检测TBT诱导的骨髓间充质干细胞分化改变对B淋巴细胞生成的影响。3.确定长期、低剂量TBT暴露对骨生理和体内B淋巴细胞生成的影响。总而言之，这些研究将有助于对淋巴生成和骨髓微环境之间的相互关系的基本理解，以及关于治疗和环境污染物如何改变导致过早衰老的骨髓生理的新的基于机制的信息。

DESCRIPTION (provided by applicant): A growing number of environmental contaminants are being recognized for their ability to activate the master regulator of adipocyte differentiation, peroxisome proliferator activated receptor ( (PPAR(), including phthalates and organotins. Tributyltin (TBT) has been a pollutant of concern in the marine environment due to its use as an anti-fouling agent; however the use of TBT in agricultural pesticides, wood preservatives and the manufacturing of plastics has resulted in significant land-based sources of this contaminant such that organotins are even measurable in house dust. Our data indicate that TBT is a highly potent activator of PPAR( in bone marrow stromal cells. The EC50 for adipocyte differentiation is ~10 nM, a concentration well within the range of organotins measured in human in liver and blood (0.1-500 nM). The bone marrow is a multifunctional organ that supports bone formation, as well as lymphopoiesis, and both functions are compromised during aging. A single mesenchymal stem cell progenitor produces both adipocytes and osteoblasts, resulting in a reciprocal relationship between adipocyte and osteoblast differentiation. As mammals age, there is an increase in fat mass within the bone marrow associated with a concomitant loss of osteoblasts. Additionally, exposure to therapeutic PPAR3 activators for treatment to Type II diabetes causes fatty bone formation in patients and increases risk for fracture. Recent literature has shown that 1) osteoblasts are necessary for optimal lymphopoiesis and 2) adipocytes are negative regulators of lymphopoiesis. A complicated balance of stromal elements and B cell precursors in the bone marrow is required to perpetuate B cell development throughout life that is particularly critical in aging mammals, in whom accumulation of fat in the bone marrow occurs concurrently with senescence of lymphopoiesis. Thus, we hypothesize that contaminant-driven activation of PPAR( and adipocyte differentiation will lead to premature aging in the bone and that accumulation of adipocytes in bone marrow and suppression of osteoblast differentiation results in loss of the ability to generate lymphocytes, as well as in loss of bone integrity. The following specific aims are designed to examine this hypothesis: 1. Determine molecular mechanisms of alteration of bone marrow mesenchymal stem cell differentiation by environmental and therapeutic PPAR(/RXR1 agonists. 2. Examine effects of TBT-induced alteration of bone marrow mesenchymal stem cell differentiation on B lymphopoiesis. 3. Define impact of long-term, low-dose TBT exposure on bone physiology and B lymphopoiesis in vivo. Collectively, these studies will contribute to both the basic understanding of the inter-relationship between lymphopoiesis and the bone marrow microenvironment, as well as contribute new mechanism-based information on how therapeutics and environmental contaminants alter the physiology of the bone marrow leading to premature aging.