The Function of PEDF in Recessive Osteogenesis Imperfecta

描述（由申请人提供）：成骨不全（OI）是最常见的脆骨病形式，其严重程度从轻度表型到重度早期致死性不等。OI的主要临床特征是骨脆性和低骨量。该奖学金的重点是一个基因，SERPINF1（丝氨酸蛋白酶抑制剂，进化枝F，成员1），其中突变导致一种独特的OI形式（VI型）。VI型OI的特征是未矿化的类骨质和鱼鳞状的骨分层，这在病理学上与其他形式的OI不同。SERPINF1编码色素上皮衍生因子（PEDF），其作为抗血管生成、神经营养和神经保护因子被广泛研究。尽管PEDF在骨骼组织的主要细胞类型中表达，包括成骨细胞、破骨细胞和软骨细胞，但其在骨稳态中的功能尚不清楚。因此，本研究的目的是阐明PEDF在骨稳态中的作用，并确定该基因无效突变导致VI型OI的机制。我还将评估外源性PEDF的治疗潜力，使用小鼠模型。在初步数据中，PEDF敲除小鼠显示出骨体积减少和MEPE表达水平增加，MEPE是骨矿化的负调节因子。基于初步的数据，我推测PEDF的丢失改变了调节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功能丧失和获得小鼠模型以及评估不存在PEDF时的细胞信号传导缺陷来验证这一假设。本研究不仅将阐明一种新的骨矿化调控机制，而且将建立VI型OI的致病机制，从而为VI型OI患者提供潜在的治疗策略。 公共卫生相关性：该项目旨在阐明丝氨酸蛋白酶抑制剂肽酶抑制剂，进化枝F，成员1（SERPINF 1）的基因的作用，该基因编码蛋白质色素上皮衍生因子（PEDF）。PEDF的损失导致VI型成骨不全（OI VI型），这是一种形式的脆骨疾病。通过本研究，我们希望发现PEDF在骨内环境稳定和VI型OI发病机制中的新功能，可能导致新的治疗靶点。

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.