Development of a novel therapy with Apolipoprotein E for osteogenesis imperfecta

开发载脂蛋白 E 治疗成骨不全症的新疗法

• 批准号: 10262928
• 负责人: Satoru Otsuru
• 金额: $ 16.49万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10262928
• 关键词: Acceleration; Address; Age; Animal Model; Apolipoprotein E; Area; Bioinformatics; Blood; Bone Diseases; Bone Growth; Brain; Cell Proliferation; Cell Therapy; Cells; Chest; Chondrocytes; Collagen; Conditioned Culture Media; Defect; Development; Epiphysial cartilage; Exhibits; Genes; Genetic; Genetic Diseases; Growth; Harvest; Heart; Impairment; In Situ Hybridization; In Vitro; Infusion procedures; Intraperitoneal Injections; Investigation; Knock-out; Knockout Mice; Lead; Length; Liver; Measures; Mediator of activation protein; Mesenchymal; Mus; Musculoskeletal; Mutate; Mutation; Organ Culture Techniques; Osteoblasts; Osteocalcin; Osteogenesis Imperfecta; Outcome; Pathogenesis; Patients; Pattern; Play; Production; Proteomics; Recombinants; Reporting; Respiratory Failure; Role; Safety; Secondary to; Serum; Solid; Stromal Cells; Symptoms; Therapeutic Effect; Wild Type Mouse; Work; bisphosphonate; bone; bone fragility; conditional knockout; effective therapy; improved; innovation; insight; mouse model; novel; novel therapeutics; postnatal; prevent; restoration; side effect; skeletal; standard care; stem; treatment strategy

Osteogenesis imperfecta (OI), known as a brittle bone disease, is a genetic disorder typically caused by a mutation in type l collagen. In addition to bone fragility, growth deficiency is a critical musculoskeletal issue of OI. There is no cure for OI. While bisphosphonates are the standard treatment to strengthen bones, there is no reliably effective treatment for growth impairment, especially in patients with severe types of OI. Previously, we and others have reported that systemic infusion of mesenchymal stem/stromal cells (MSC) can stimulate bone growth in OI patients as well as in OI model mice. Despite this striking growth acceleration, the therapeutic effects were transient. Moreover, MSC therapy has several inherent limitations such as inconsistent results between different MSC donors, need for Good Manufacturing Practice facilities, and safety concerns of culture- expanded cellular infusions. Thus, identifying the mechanism of MSC-induced bone growth is critical to develop novel cell-free therapies that can be safely and repeatedly implemented during the growth period in OI patients. Our investigation revealed that MSC-induced bone growth was not a direct effect of MSCs themselves; rather, MSC infusion induced production of a factor(s) in the serum which stimulated chondrocyte proliferation in the growth plate and resulted in linear bone growth. Proteomic and bioinformatics analyses of the serum from MSC infused mice identified apolipoprotein E (ApoE) as a primary candidate for the factor. Our preliminary studies demonstrated that ApoE serum levels were significantly elevated after MSC infusion and recombinant ApoE markedly stimulated chondrocyte proliferation and hypertrophic differentiation in chondrocyte culture. Moreover, ApoE enhanced bone growth in ex vivo organ culture. These findings were strongly supported by compelling evidence that ApoE knockout mice display significantly shorter bones than wild type mice. Collectively, these findings provide rigorous premises for our highly innovative hypothesis that ApoE can improve bone growth deficiency by stimulating chondrocyte proliferation and differentiation in the OI growth plate. Additionally, it has been shown that ApoE is produced by mature osteoblasts. In OI, mutated Col1 expression prevents osteoblasts from maturation and as a result, the number of mature osteoblasts is significantly reduced. Interestingly, our preliminary study showed that ApoE levels in bones were significantly lower in OI mice than wild type controls. These findings suggest that reduced production of ApoE by OI osteoblasts may play a critical role in the pathogenesis of OI growth deficiency. Thus, we propose the following specific aims: (1) to determine the therapeutic effects of ApoE for growth deficiency in OI; and (2) to examine the role of ApoE produced by osteoblasts in growth plate function and bone growth. The completion of these aims will determine whether ApoE can serve as a novel therapeutic molecule to enhance bone growth in OI and provide novel insights to identify the pathogenesis of OI growth deficiency. This exploratory project has the potential to completely revolutionize the treatment strategy for OI.

成骨不全症（OI），又称脆骨病，是一种遗传性疾病，通常由骨质疏松引起