OSTEOGENESIS IMPERFECTA, AND NITRIC OXIDE THERAPY

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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.