Imaging evidence: Is there competition between marrow fat and bone?

描述（申请人提供）：骨质疏松症是美国主要的健康问题之一。最近的研究表明，骨髓中的脂肪细胞和成骨细胞具有相同的前体，间充质干细胞（MSC）。人体影像学研究[即磁共振波谱（MRS）、磁共振成像（MRI）和计算机断层扫描（CT）]也表明，骨髓脂肪组织（BMAT）和骨矿物质密度（BMD）之间存在反比关系。目前尚不清楚这种反向关系是否代表了基质细胞从成骨细胞向脂肪细胞的优先分化，或者随着年龄的增长，骨骼丢失和骨髓空间增加而被动积累脂肪。明确骨矿物质与骨髓脂肪之间的关系是通过增强祖细胞的成骨分化来预防和治疗骨质流失的关键的第一步。这项研究汇集了一个独特的数据库，大约1000名健康成年人都有全身MRI和DXA数据，否则收集这些数据非常昂贵。该研究的目的是在不同受试者的数据库中研究全身MRI的BMAT和双能x线吸收仪（DXA）的BMD之间的关系。以往使用MRS和CT方法的研究通常局限于测量单个骨内小体积的BMAT。与我们的全身MRI方法相比，使用MRS量化BMAT的研究报告BMAT和骨密度之间的相关性较低，原因之一是单个骨腔或跨骨的BMAT缺乏均匀性。我们提出的MRI方法克服了MRS或CT方法的采样限制，具有独特的能力，可以研究多发性松质骨的BMAT。这项拟议的研究将检验已经达到或接近骨量峰值的年轻人和潜在骨质流失的老年人的骨密度和骨密度之间的关联是否存在差异。如果在年轻/峰值骨量受试者和老年/潜在骨质流失受试者中BMAT和骨密度之间存在强烈的负相关，那么结果将支持低骨密度与基质细胞从成骨细胞向脂肪细胞优先分化有关的假设。或者，如果BMAT和骨密度之间存在强烈的负相关关系仅存在于潜在骨质流失的老年人中，而不存在于年轻人中，那么脂肪的被动积累或MSC从成骨细胞向脂肪细胞的优先分化可以解释与衰老相关的病理生理。此外，这种独特多样的大规模MRI和DXA数据库将使我们能够首次系统地研究骨髓脂肪之间关系的潜在性别和种族差异。这些研究的发现将有助于理解骨髓脂肪和骨骼之间的相互作用，并将补充和指导正在进行的分子研究和药物开发研究作为临床证据。公共卫生相关性：作为先前资助的身体成分研究的一部分，将使用成像软件分析大约1000个存档的全身磁共振成像（MRI）扫描的大型数据库，以量化每个受试者扫描的骨髓脂肪。通过比较年轻和老年受试者骨髓脂肪和骨矿物质之间的关系，将获得骨髓脂肪和骨矿物质之间是否存在竞争关系的重要证据，这将补充分子水平的研究。

DESCRIPTION (provided by applicant): Osteoporosis is one of the leading health problems in the United States. Recent studies suggest that adipocytes in bone marrow and osteoblasts share the same precursor, mesenchymal stem cells (MSC). Human imaging studies [i.e., magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI) and computed tomography (CT)] have also shown that there is an inverse relationship between bone marrow adipose tissue (BMAT) and bone mineral density (BMD). It is unknown whether this inverse relationship represents a preferential differentiation of stromal cells from osteoblasts to adipocytes, or a passive accumulation of fat as bone is lost and marrow space increases with aging. A clearer understanding of the relationship between bone mineral and marrow fat is a critical first step towards the development of prevention and treatment strategies for bone loss through enhancing the osteogenic differentiation of progenitor cells. This study pools a unique database of ~1000 healthy adults all of whom have both whole body MRI and DXA data which are otherwise very expensive to collect. The proposed aim is to investigate the relationship between BMAT by whole body MRI and BMD by dual-energy x-ray absorptiometry (DXA) in a subject-diverse database. Previous studies using MRS and CT methods are usually limited to measuring BMAT in a small volume usually within a single bone. Lack of BMAT homogeneity in the cavity of a single bone or across bones presents as one of the reasons why studies using MRS to quantify BMAT report a lower correlation between BMAT and BMD compared to our whole body MRI methods. Our proposed MRI methods overcome the sampling limitations of MRS or CT methods by possessing the unique ability to allow for the study of BMAT of multiple cancellous bones. The proposed study will examine whether there are differences between the association of BMAT and BMD in young adults who have achieved or are close to their peak bone mass and older adults with potential bone loss. If there is a strong inverse correlation between BMAT and BMD in both younger/peak bone mass subjects and older/potential bone loss subjects, the results would support the hypothesis that lower BMD is related to a preferential differentiation of stromal cells from osteoblasts to adipocytes. Alternatively, if a strong inverse relationship between BMAT and BMD exists only in older adults who potentially have bone loss but not in younger adults, either passive accumulation of fat or preferential differentiation of MSC from osteoblasts to adipocytes could explain the pathophysiology related to aging. Furthermore, this unique diverse large scale MRI and DXA database will allow us to first systematically investigate potential gender and ethnic differences in the relationship between bone and marrow fat. The findings from these studies will contribute significantly to understanding the interplay between marrow fat and bone and will complement and provide direction for ongoing molecular studies and drug development studies as clinical evidence. PUBLIC HEALTH RELEVANCE: A large database of approximately 1000 archived whole body magnetic resonance imaging (MRI) scans collected as part of previously funded body composition studies will be analyzed using imaging software to quantify bone marrow fat in each subject scan. By comparing the relationship between marrow fat and bone mineral in younger and older subjects, important evidence will be obtained on whether there is a competitive relationship between marrow fat and bone mineral which will complement molecular level studies.