The Function of PEDF in Recessive Osteogenesis Imperfecta

描述(由申请人提供)：成骨不全(OI)是最常见的脆性骨骼疾病，表现出从轻微表型到严重早期死亡的一系列严重程度。OI的主要临床特征是骨脆性和骨量低。这项研究的重点是一种名为SERPINF1(丝氨酸肽酶抑制因子，分支F，成员1)的基因，在该基因中，突变会导致一种独特的OI(VI型)。VI型OI以未矿化的类骨质和鱼鳞状骨片为特征，在病理上有别于其他类型的OI。SERPINF1编码色素上皮衍生因子(PEDF)，是一种广泛研究的抗血管生成、神经营养和神经保护因子。尽管PEDF在成骨细胞、破骨细胞和软骨细胞等骨骼组织的主要细胞类型中表达，但其在骨稳态中的作用尚不清楚。因此，本研究的目的是阐明PEDF在骨内稳态中的作用，并确定该基因零突变导致OI VI型的机制。我还将利用小鼠模型评估外源性PEDF的治疗潜力。在初步数据中，PEDF基因敲除小鼠表现出骨体积减少和MEPE表达水平增加，MEPE是骨矿化的负面调节因子。根据初步数据，我假设PEDF的丢失改变了调控成骨细胞和骨细胞功能的细胞内信号，从而导致异常的骨矿化。我将通过研究PEDF功能丧失和功能获得的小鼠模型，以及在没有PEDF的情况下评估细胞信号缺陷来检验这一假设。本研究不仅将阐明新的骨矿化调控机制，而且将为OI VI的发病机制奠定基础，从而为OI VI患者提供潜在的治疗策略。 与公共健康相关：该项目旨在阐明编码蛋白质色素上皮衍生因子(PEDF)的基因，丝氨酸肽酶抑制因子，分支F，成员1(SERPINF1)的作用。PEDF的缺失导致VI型成骨不全(OI VI型)，这是一种脆性骨病。通过本研究，我们希望发现PEDF在骨内稳态中的新功能和OI VI型的发病机制，为治疗提供新的靶点。

DESCRIPTION (provided by applicant): Osteogenesis Imperfecta (OI) is the most common form of brittle bone disease and displays a spectrum of severity from mild phenotypes to severe early lethality. Key clinical features of OI are bone fragility and low bone mass. This fellowship focuses on a gene, SERPINF1 (serpin peptidase inhibitor, clade F, member 1), in which mutations cause a unique form of OI (type VI). OI type VI is characterized by un- mineralized osteoid and the fish-scale pattern of bone lamellation, which are pathologically distinct from other forms of OI. SERPINF1 encodes pigment epithelium-derived factor (PEDF) which is extensively studied as an anti-angiogenic, neurotrophic, and neuroprotective factor. Although PEDF is expressed in major cell types of skeletal tissue including osteoblasts, osteoclasts, and chondrocytes, its function in bone homeostasis is unknown. Therefore, the goal of this proposal is to elucidate the role of PEDF in bone homeostasis and determine the mechanism by which null mutations of this gene lead to OI type VI. I will also evaluate the therapeutic potential of exogenously delivered PEDF using mouse models. In the preliminary data, PEDF knockout mice show reduced bone volume and increased the expression level of MEPE, a negative regulator of bone mineralization. Based on preliminary data, I hypothesize that loss of PEDF alters intracellular signaling which regulates the function of osteoblasts and osteocytes, thus resulting in abnormal bone mineralization. I will test this hypothesis by investigating the PEDF loss- and gain-of-function mouse models and by evaluating cell signaling defects in the absence of PEDF. This research will not only elucidate a novel regulatory mechanism for bone mineralization, but also establish the pathogenic mechanism of OI type VI, thus providing potential therapeutic strategies for patients with OI type VI. PUBLIC HEALTH RELEVANCE: This project serves to elucidate the role of the gene, serpin peptidase inhibitor, clade F, member 1, (SERPINF1) which encodes the protein pigment epithelium-derived factor (PEDF). The loss of PEDF results in Osteogenesis Imperfecta type VI (OI type VI) which is a form of brittle bone disease. Through this research we hope to discover novel function of PEDF in bone homeostasis and pathogenic mechanism of OI type VI, potentially leading to new targets for therapeutics.