Defining the role of fibulin-1 in bone formation and bone repair

 描述(申请人提供)：严重骨折患者的生理性修复通常会导致骨不完全闭合。BMP-2已在临床上用于促进骨修复。然而，即使使用BMP-2，一种强烈的成骨细胞分化诱导剂，获得完全的骨关闭仍然是一个问题。此外，目前的治疗方法已经导致了多种医学并发症，这是由于促进骨修复所需的BMP-2的超生理水平。因此，有必要确定新的候选材料，以提高BMP-2在骨愈合中的疗效。需要高浓度的BMP-2的部分原因是我们对细胞外基质(ECM)在骨修复过程中BMP-2信号转导中的作用了解有限。鉴于已知的相对大量的ECM蛋白可以负向调节BMP-2介导的骨形成，确定BMP-2信号的正向ECM调节器是很重要的。我们最近报道，细胞外基质蛋白纤维蛋白-1(Fbln1)是骨形成的正向调节因子，与BMP-2结合并促进成骨细胞分化。为了进一步了解Fbln1在骨形成中的作用机制，以及Fbln1在骨再生中的作用，我们提出了两个具体的目标：1)确定纤维蛋白-1中负责BMP-2介导的Osterix和BMP-2结合的区域(S)；2)确定是否需要纤维蛋白-1来修复临界大小的颅骨缺损。

 DESCRIPTION (provided by applicant): The physiological repair of severe bone fractures in patients often results in incomplete bone closure. Bmp-2 has been used clinically to improve bone repair. However even with the use of Bmp-2, a strong inducer of osteoblast differentiation, obtaining complete bone closure is still a problem. Moreover, current treatments have led to multiple medical complications due to supra-physiological levels of Bmp-2 required to promote repair bone. Therefore there is a need to identify new candidates that can improve Bmp-2 efficacy in bone healing. High concentrations of Bmp-2 are required in part because of our limited understanding of the role the extracellular matrix (ECM) plays in Bmp-2 signaling during bone repair. Given the relatively large number ECM proteins known to negatively regulate Bmp-2-mediated bone formation it is important to identify positive ECM modulators of Bmp-2 signaling. We have recently reported that the ECM protein, Fibulin-1 (Fbln1) is a positive modulator of bone formation that binds Bmp-2 and acts to promote osteoblast differentiation. In order to further our mechanistic understanding of Fbln1 in bone formation and address the role of Fbln1 in bone regeneration we have proposed two specific aims 1) Define the region(s) within Fibulin-1 responsible for Bmp-2-mediated induction of Osterix and Bmp-2 binding 2) Determine if Fibulin-1 is required for repair of critical size calvarial defects.