FGFs in skeletal development, vasculogenesis and repair

描述（由申请人提供）：骨骼骨折是人类发病率的重要因素。此外，在老龄化人口中，骨质疏松症发病率的增加与骨骼损伤有关，如髋部骨折，导致相当大的死亡率。因此，了解骨折修复和骨骼对机械应力的反应的机制和分子是很重要的。编码FGF受体（FGFRs） 1、2和3的基因中大量错义突变是许多人类颅缝闭锁和软骨发育不良综合征的病因，这说明了FGF信号在骨骼生物学中的重要性。此外，小鼠FGFRs 1、2和3的功能缺失和骨骼特异性条件功能缺失突变也显示出骨骼发育和成骨结构和完整性的特异性缺陷。本文提出的研究应该为操纵FGF信号治疗骨骼损伤和疾病提供指导。与我们对fgfr在骨骼形成中的功能的日益了解相反，关于FGF配体调节骨骼发育、生长、重塑、血管生成和修复的信息很少。缺乏FGF2 （bFGF）的成年小鼠骨密度轻度下降，但骨骼没有形态学缺陷。缺乏FGF18的小鼠在出生时死亡，并表现出中度骨骼畸形。这些小鼠也有骨化中心的延迟形成，这种表型在成骨细胞或软骨细胞中缺乏FGFRs 1、2或3的小鼠中未见。最近，我们在缺乏FGF9的小鼠中发现了一种骨骼表型。这些数据表明，FGF18（以及潜在的FGF9）向骨骼细胞（软骨细胞和成骨细胞）发出信号，调节早期骨骼发育，并向非骨骼间充质细胞发出信号，调节骨骼周围血管的形成和生长板的血管侵袭。在本提案中，我们将：1)验证Fgf9， Fgf18和可能的Fgf2在骨骼发育，修复和机械负荷响应过程中表达模式冗余的假设；2)我们将描述缺乏FGF9、FGF18以及FGF9和FGF18的小鼠的骨骼表型，我们将确定FGF2是否与FGF9和FGF18有冗余相互作用；3)我们将确定FGF9和FGF18调控软骨内骨血管化的机制；4)我们将验证在机械负荷下，FGF信号是皮质骨形成和相关骨膜血管化增加所必需的假设。

DESCRIPTION (provided by applicant): Skeletal fracture contributes to significant morbidity throughout the human population. Furthermore, in our aging population, the increased incidence of osteoporosis is associated with skeletal injuries, such as hip fractures, resulting in considerable mortality. It is thus important to understand the mechanisms and the molecules involved in fracture repair and the response of the skeleton to mechanical stress. The importance of FGF signaling in skeletal biology is illustrated by the large number of missense mutations in the genes encoding FGF receptors (FGFRs) 1, 2 and 3 that are the etiology of many human craniosynostosis and chondrodysplasia syndromes. Furthermore, loss of function and skeletal-specific conditional loss of function mutations in mouse FGFRs 1,2 and 3 also show specific defects in skeletal development and in the structure and integrity of adult bone. The studies proposed here should provide guidance for the potential manipulation of FGF signaling to treat skeletal injury and disease. In contrast to our increasing understanding of the function of FGFRs in skelatogenesis, there is little information on the FGF ligands that regulate skeletal development, growth, remodeling, vasculogenesis and repair. Adult mice lacking FGF2 (bFGF) have a mild decrease in bone mineral density but no morphological defects in their skeleton. Mice lacking FGF18 die at birth and show moderate skeletal dismorphology. These mice also have a delayed formation of ossification centers, a phenotype not seen in mice lacking FGFRs 1, 2 or 3 in osteoblasts or chondrocytes. Recently, we have identified a skeletal phenotype in mice lacking FGF9. These data suggest that FGF18 (and potentially FGF9) signals to both skeletal cells (chondrocytes and osteoblasts) to regulate early skeletal development and to non-skeletal mesenchymal cells to regulate peri-skeletal vasculogenesis and vascular invasion of the developing growth plate. In this proposal we will: 1) Test the hypothesis that Fgf9, Fgf18 and possibly Fgf2 have redundancy in expression patterns during skeletal development, repair and response to mechanical loading; 2) We will characterize the skeletal phenotypes of mice lacking FGF9, FGF18 and both FGF9 and FGF18 and we will determine whether FGF2 has redundant interactions with FGF9 and FGF18; 3) We will determine the mechanism by which FGF9 and FGF18 regulate vascularization of endochondral bone; 4) We will test the hypothesis that in response to mechanical load, FGF signaling is required for cortical bone formation and associated increased periosteal vascularization.