OSTEOGENESIS IMPERFECTA, AND NITRIC OXIDE THERAPY

成骨不全和一氧化氮疗法

• 批准号: 7477733
• 负责人: Philip A Osdoby
• 金额: $ 16.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477733
• 关键词: Affect; Architecture; Blood Pressure; Blood Vessels; Bone Density; Bone Development; Bone Resorption; Bone Resorption Inhibition; Bone remodeling; Categories; Cell Communication; Cells; Characteristics; Childhood; Class; Collagen; Collagen Type I; Connective Tissue; Deformity; Disease; Endothelium; Ethnic group; Exons; Extracellular Matrix; Female; Fracture; Frequencies; Goals; Growth; Human; In Vitro; Incidence; Knock-in Mouse; Lead; Learning; Link; Mechanics; Modeling; Modification; Molecular; Mus; Mutation; Nature; Neuromuscular Manifestations; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Numbers; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis Imperfecta; Other Genetics; Pathology; Phenotype; Physiological; Physiology; Platelet aggregation; Play; Postmenopausal Osteoporosis; Process; Property; Range; Recruitment Activity; Research; Role; Severities; Signal Transduction; Signaling Molecule; Site; Skeletal system; Skeleton; Stimulus; TNFSF11 gene; Testing; Therapeutic Agents; Therapeutic Effect; Tissues; Vascular remodeling; angiogenesis; bisphosphonate; bone; bone loss; bone turnover; early onset; heritable connective tissue disorder; improved; in vivo; male; mouse model; novel; novel strategies; prevent; racial and ethnic; repaired; response

DESCRIPTION (provided by applicant): Type I collagen mutations occurring in the majority of cases of osteogenesis imperfecta (OI) cause a broad range of phenotypes depending upon the mutational site and nature of the mutations (eg. what residue substitutes for Gly or if exon skipping occurs), hetero- or homozygosity of the mutation, and other genetic and physiological variables. The four predominant OI (Type I-IV) classes and the three more recent (Type V-VII) novel OI categories demonstrate various skeletal, connective tissue, and neuromuscular manifestations. Common OI skeletal characteristics that vary in degree, duration, and onset include diminished skeletal growth, decreased bone density, bone deformity, and an increased incidence of fractures. Alterations in collagen matrices due to OI mutations result in abnormal extracellular matrix properties and interactions with other matrix molecules or cells in bone, vascular, and other tissues. In bone, this may lead to enhanced bone turnover, alterations in osteoclast, osteoblast and/or osteocyte numbers, and a net loss of bone. The recruitment and activity of osteoclasts and osteoblasts are intimately linked with the bone vasculature, and the latter therefore plays critical roles throughout normal bone development, formation, remodeling, and repair, while pathological alterations in bone vasculature impact these processes in various skeletal diseases. OI-related vascular disturbances (eg. loss of vessel integrity, impaired vascular invasion, changes in vascular phenotype, architecture or function) are less well studied but may also appear in the early onset pre-pubertal forms of OI (Types III and IV), potentially indicating functional interrelationships between bone resorption/remodeling and vascular-associated changes in OI pathology. Typically, OI is treated with anti-resorptive bisphosphonates, agents that have proven partially successful for reducing the severity of OI-related bone loss and fracture frequency. However, administration of such long-lasting anti-resorptive bisphosphonates in the growing pediatric skeleton is of some increasing concern. Consequently, improved strategies and therapeutic agents to manage and alleviate OI-associated bone loss, deformity, and fracture frequency are needed. One possible novel approach proposed here focuses on the administration of nitric oxide (NO), a key signal molecule known to exert major vasculoprotective, as well as osteoprotective, roles in normal physiology and pathology. In the vasculature, NO importantly regulates blood pressure, angiogenesis, platelet aggregation, circulating cell interactions with the endothelium, and other critical processes. In bone, NO-related research in the last decade has uncovered compelling evidence that physiological levels of NO evoke multiple osteoprotective responses, ranging from transduction of mechanical stimuli into osteoblast anabolic responses, modification of bone angiogenesis, suppression of osteoclast- inductive RANKL expression and signaling, and inhibition of bone resorption by mature osteoclasts in vitro and in vivo. NO therapy, supplied via a non-toxic NO donor substance like nitroglycerin, is emerging as a potential safe and effective anti-resorptive treatment for postmenopausal osteoporosis, on par with bisphosphonates. We hypothesize that NO therapy might be an effective alternative to bisphosphonates for treating OI. Therefore, a primary goal of this proposal is to test the efficacy of NO therapy in a well-characterized murine knock-in model (BrtlIV) of human Type IV OI to learn if it improves skeletal osteopenia and accompanying fracture frequency. A second goal will be to investigate molecular mechanisms through which NO may exert OI therapeutic effects, including the potential for NO to inhibit osteoclast/osteoblast bone remodeling processes that may contribute to the osteopenia associated with OI Osteogenesis Imperfecta is a heritable connective tissue disorder characterized by increased bone fragility ("brittle bone") that affects both males and females equally and occurs across all racial and ethnic groups. A primary goal of this proposal is to test the efficacy of nitric oxide (nitroglycerin) therapy in a well-characterized mouse model of human Type IV OI to learn if Nitric oxide therapy improves skeletal osteopenia and accompanying fracture frequency in osteogenesis imperfecta.

描述（由申请人提供）：在大多数成骨细胞（OI）病例中发生的I型胶原突变会导致广泛的表型，这取决于突变位点和突变性质（例如，什么残基替代Gly或是否发生外显子跳跃）、突变的杂合性或纯合性以及其他遗传和生理变量。四种主要的OI（I-IV型）类别和三种最近的（V-VII型）新OI类别表现出各种骨骼、结缔组织和神经肌肉表现。在程度、持续时间和发作方面不同的常见OI骨骼特征包括骨骼生长减缓、骨密度降低、骨畸形和骨折发生率增加。由于OI突变引起的胶原基质的改变导致异常的细胞外基质性质以及与骨、血管和其他组织中的其他基质分子或细胞的相互作用。在骨中，这可能导致骨转换增强，破骨细胞、成骨细胞和/或骨细胞数量改变，以及骨的净损失。破骨细胞和成骨细胞的募集和活性与骨血管系统密切相关，因此后者在正常骨发育、形成、重塑和修复过程中起关键作用，而骨血管系统的病理学改变影响各种骨骼疾病中的这些过程。OI相关血管紊乱（例如，血管完整性丧失、血管侵袭受损、血管表型、结构或功能变化）的研究较少，但也可能出现在早发性青春期前形式的OI（III型和IV型）中，这可能表明骨吸收/重塑与OI病理学中血管相关变化之间的功能相互关系。通常情况下，OI是用抗再吸收双膦酸盐治疗的，这些药物已被证明部分成功地降低了OI相关骨丢失的严重程度和骨折频率。然而，这种长效抗吸收双膦酸盐在儿童骨骼发育中的应用越来越受到关注。因此，需要改进的策略和治疗剂来管理和减轻OI相关的骨丢失、畸形和骨折频率。这里提出的一种可能的新方法集中在一氧化氮（NO）的管理，一个关键的信号分子，已知发挥主要的血管保护，以及骨保护，在正常的生理和病理作用。在脉管系统中，NO重要地调节血压、血管生成、血小板聚集、循环细胞与内皮的相互作用以及其他关键过程。在骨中，过去十年中NO相关的研究已经发现了令人信服的证据，即生理水平的NO引起多种骨保护反应，范围从机械刺激到成骨细胞合成代谢反应的转导，骨血管生成的修饰，破骨细胞诱导RANKL表达和信号传导的抑制，以及体外和体内成熟破骨细胞对骨吸收的抑制。通过无毒的NO供体物质（如硝酸甘油）提供的NO治疗正在成为绝经后骨质疏松症的潜在安全有效的抗吸收治疗，与双膦酸盐相当。我们假设NO治疗可能是双膦酸盐治疗OI的有效替代方案。因此，该提议的主要目标是在人IV型OI的良好表征的鼠基因敲入模型（BrtlIV）中测试NO疗法的功效，以了解其是否改善骨骼骨量减少和伴随的骨折频率。第二个目标是研究NO发挥OI治疗作用的分子机制，包括NO抑制破骨细胞/成骨细胞骨重塑过程的潜力，该过程可能导致与OI相关的骨质减少成骨不全是一种以骨脆性增加为特征的遗传性结缔组织疾病骨质疏松症（“脆骨”），对男性和女性的影响相同，发生在所有种族和族裔群体中。本提案的主要目的是在人IV型OI的良好表征的小鼠模型中测试一氧化氮（硝酸甘油）治疗的功效，以了解一氧化氮治疗是否改善骨生成障碍中的骨骼骨量减少和伴随的骨折频率。