The Function of PEDF in Recessive Osteogenesis Imperfecta

描述（由申请人提供）：成骨不全症（Osteogenesis Imperfecta， OI）是最常见的脆性骨病，表现出从轻度表型到严重的早期致死率的严重程度。成骨不全的主要临床特征是骨脆性和低骨量。这项研究的重点是一个基因，serinf1（丝氨酸肽酶抑制剂，进化支F，成员1），其突变导致一种独特形式的OI （VI型）。VI型成骨不全以非矿化的类骨和鱼鳞状骨片状为特征，在病理上与其他形式的成骨不全不同。serinf1编码色素上皮衍生因子（PEDF）， PEDF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，本提案的目标是阐明PEDF在骨稳态中的作用，并确定该基因的零突变导致VI型成骨不全的机制。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敲除小鼠表现出骨体积减小和骨矿化负调节因子MEPE表达水平升高。根据初步数据，我推测PEDF的缺失改变了细胞内信号传导，从而调节成骨细胞和骨细胞的功能，从而导致骨矿化异常。我将通过研究PEDF缺失和功能获得的小鼠模型以及评估PEDF缺失时的细胞信号缺陷来验证这一假设。本研究不仅将阐明骨矿化的新调控机制，还将建立VI型成骨不全的致病机制，从而为VI型成骨不全患者提供潜在的治疗策略。

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.