ARCHITECTURAL MICROFIBRILS IN BONE PHYSIOLOGY

描述（由申请人提供）：我们试图了解细胞外微原纤维对骨生理学的贡献，并隐含地阐明马凡综合征（MFS）和先天性挛缩性蛛网膜下腔畸形（CCA）骨骼表现的病理基础。MFS和CCA分别是由微原纤维的主要结构成分纤维蛋白1和2的突变引起的。细胞外微原纤维，单独或联合弹性蛋白作为弹性纤维，构成包括骨骼在内的多个器官系统的结构支架。在过去的资助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，部分是由于信号事件失调和细胞表现异常。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平衡，在不同程度上影响骨形成和骨吸收。因此，我们假设在骨骼中微纤维缺陷的程度与失调信号和细胞反应的水平之间存在因果关系。与I型胶原蛋白突变对骨功能的影响类似，我们也假设纤维蛋白突变可能会对这些建筑基质成分赋予骨组织材料和结构特性的能力产生负面影响。因此，当前应用的前提是基于创新的、基于证据的假设，即建筑微原纤维在骨生理学中起着两种不同的作用——信号分子调节骨形成、生长和更新的作用，以及为基质提供结构支持以赋予骨强度的作用。因此，我们建议利用纤维蛋白突变小鼠来(a)表征导致纤维蛋白1表达不足或缺乏纤维蛋白2的小鼠骨量减少的细胞缺陷的特性和性质；(b)阐明纤维蛋白1和2在皮质骨形成中的不同作用；(c)评估富含纤维蛋白的微原纤维分级丢失对基质组织、材料质量和骨和软骨生物力学性能的影响。所提出的研究的意义在于，对骨骼中原纤维蛋白功能的理解将为该器官系统中常驻细胞和建筑基质之间不明确的关系提供新的线索。这项拨款申请的长期目标是产生基础科学信息，这些信息将有利于设计合理的治疗马凡氏综合征患者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.