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. ? ? ?
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