ARCHITECTURAL MICROFIBRILS IN BONE PHYSIOLOGY

描述(申请人提供)：我们试图了解细胞外微纤维对骨生理学的贡献，并隐含地阐明马凡综合征(MFS)和先天性宫缩蛛网膜炎(CCA)骨骼表现的病理基础。MFS和CCA分别是由纤维蛋白1和纤维蛋白2的突变引起的，纤维蛋白1和2是微纤维的主要结构成分。细胞外微纤维单独或与弹性蛋白一起作为弹性纤维，构成包括骨骼在内的多个器官系统的建筑支架。在过去的资金周期中取得的进展表明，纤维蛋白病的疾病进展部分是由于组织完整性的丧失，部分是由于失调的信号事件和异常的细胞性能。初步研究表明，纤维蛋白-1和纤维蛋白-2缺乏通过改变控制骨量维持的局部信号的平衡，在不同程度上影响骨形成和骨吸收。因此，我们假设骨骼中微纤维缺陷的程度与失调的信号和细胞反应水平之间存在因果关系。通过类比I型胶原突变对骨功能的影响，我们还假设，纤维蛋白突变可能会对建筑基质的这些成分向骨骼组织赋予材料和结构属性的能力产生负面影响。因此，本应用的前提是基于创新的循证假设，即建筑微纤维在骨生理学中扮演着两个不同的角色--信号分子的调节作用，以调节骨的形成、生长和周转，以及为基质提供骨强度的结构支撑的作用。因此，我们建议利用纤维蛋白突变小鼠来(A)鉴定导致表达纤维蛋白-1不足或缺乏纤维蛋白-2的小鼠骨量减少的细胞缺陷的身份和性质；(B)阐明纤维蛋白1和纤维蛋白2在皮质骨形成中的不同作用；以及(C)评估富含纤维蛋白的微纤维的逐渐丧失对骨和软骨的基质组织、材料质量和生物力学性能的影响。所提出的研究的意义在于，了解骨骼中的纤维蛋白功能将为这个器官系统中的驻留细胞和建筑基质之间的模糊关系提供新的线索。这项赠款申请的长期目标是产生基本的科学信息，这些信息将有助于为受马凡综合征影响的患者设计合理的骨矿物质替代疗法，并将提高我们对骨质疏松症易感因素的性质的理解。

DESCRIPTION (provided by applicant): We seek to understand the contribution of extracellular microfibrils to bone physiology and implicitly, to elucidate the pathological underpinning of skeletal manifestations in Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA). MFS and CCA are respectively caused by mutations in fibrillins 1 and 2, the major structural components of microfibrils. Extracellular microfibrils, alone or in association with elastin as elastic fibers, constitute the architectural scaffold of multiple organ systems, including the skeleton. Progress during the past funding cycle has revealed that disease progression in fibrillinopathies is accounted for in part by loss of tissue integrity and in part by dysregulated signaling events and abnormal cell performance. Preliminary studies suggest that fibrillin-1 and fibrillin-2 deficiencies affect bone formation and resorption to different extents by altering the balance of local signals that control maintenance of bone mass. We therefore hypothesize that a causal relationship exists in the skeleton between the extent of the microfibril defect and the levels of dysregulated signaling and cellular responses. By analogy to the consequences of collagen I mutations on bone function, we also postulate that fibrillin mutations may negatively impact on the ability of these components of the architectural matrix to confer material and structural properties to skeletal tissue. The premise of the present application therefore rests on the innovative, evidence-based hypothesis that architectural microfibrils play two distinct roles in bone physiology - the role of regulators of signaling molecules to modulate bone formation, growth and turnover, and the role of a structural support for the matrix to impart bone strength. Accordingly, we propose to utilize fibrillin mutant mice to (a) characterize the identity and nature of the cellular defects responsible for reduced bone mass in mice underexpressing fibrillin-1 or lacking fibrillin-2; (b) elucidate the differential roles of fibrillins 1 and 2 in cortical bone formation; and (c) assess the impact of graded loss of fibrillin-rich microfibrils on matrix organization, material quality and biomechanical properties of bone and cartilage. The significance of the proposed studies is that an understanding of fibrillin function in the skeleton will shed new light on the ill-defined relationship between resident cells and the architectural matrix in this organ system. The long-term goal of this grant application is to generate basic science information that will benefit the design of rational therapies for bone mineral replacement in patients affected with Marfan syndrome, and which will improve our understanding of the nature of predisposing factors in osteoporosis.