Browsing by Subject "Osteoporosis"
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Item Embargo Adenosine Delivery to Mitigate Bone Disorders(2023) Newman, HunterBone is a dynamic tissue which continuously undergoes remodeling primarily through osteoblast-mediated bone formation and osteoclast-mediated bone resorption. This balance is vital in maintaining both bone homeostasis and bone regeneration. With the increase in the global elderly population, the two most prominent bone disorders of fracture and osteoporosis pose a tremendous burden to the healthcare system. While these bone disorders are increasing in prevalence, treatment options remain stagnant, demonstrating the unmet need for new clinical solutions. Strategies that induce innate repair yet eliminate the need for expensive cellular or recombinant protein-based therapies are appealing. Adenosine, a naturally occurring nucleoside, has emerged as a part of key metabolic pathway that regulates bone tissue formation, function, and homeostasis. In this dissertation, I investigate the therapeutic potential of adenosine delivery to mitigate bone disorders. Despite the regenerative capacity of bone, age-associated changes result in injuries that suffer delayed healing. Therapeutic interventions that circumvent the age-associated impairments in bone tissue and promote healing are attractive options for geriatric fracture repair. Herein, I examined the changes in extracellular adenosine signaling with aging and the potential of local delivery of adenosine to promote fracture healing in aged mice. My results showed a concomitant reduction of CD73 expression in the bone and marrow of aged mice. Local delivery of adenosine using injectable microgel building blocks and drug carriers yielded a pro-regenerative environment and promoted fracture healing in aged mice. This study provides new understandings of age-related physiological changes in adenosine levels and demonstrates the therapeutic potential of local delivery of adenosine at the fracture site to circumvent the impaired healing capacity of aged fractures. Given the multi-functionality of adenosine signaling, it is possible that extracellular adenosine delivery influences various phases of bone healing. Towards this, I examined the potential immunomodulatory effect of adenosine delivery on both the local and systemic immune system for fracture repair. My results indicated that the immune cell populations of neutrophils and macrophages did not change with adenosine treatment in the fractured callus at either 3-, 7-, or 14-days post fracture. Additionally in the peripheral blood, CD8+ and CD4+ T cell populations did not change at any of the timepoints following adenosine treatment. This study provides potential insight into the role of exogenous adenosine in the inflammatory stage of fracture healing in young animals. Aging not only poses a risk for delayed fracture healing, but also for the development of osteoporosis. Osteoporosis results in bone fragility and subsequently a higher risk for fracture incidence. This disease is characterized by an imbalance in the coupled bone remodeling process with enhanced osteoclastic activity can lead to excessive bone resorption, resulting in bone thinning. Once activated, osteoclasts bind to the bone surface and acidify the local niche. This acidic environment could serve as a potential trigger for the delivery of therapeutic agents into the osteoporotic bone tissue. To this end, I developed a pH-responsive nanocarrier-based drug delivery system that binds to the bone tissue and delivers the osteoanabolic molecule, adenosine. Adenosine is incorporated into a hyaluronic acid (HA)-based nanocarrier through a pH-sensitive ketal group. The HA-nanocarrier was further functionalized with alendronate moieties to improve binding to the bone tissues. Systemic administration of the nanocarrier containing adenosine attenuated bone loss in an ovariectomized mice model of osteoporosis and showed comparable bone qualities to that of healthy mice. Delivery of osteoanabolic small molecules, such as adenosine, that can contribute to bone formation and inhibit excessive osteoclast activity by leveraging the tissue-specific milieu could serve as viable therapeutics for osteoporosis. Overall, this dissertation offers novel findings regarding adenosine as a therapeutic to treat both fractures and osteoporosis. These findings, along with the biomaterial delivery systems developed, further advance the potential of using adenosine as a therapeutic molecule to treat bone disorders.
Item Open Access Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model.(PLoS One, 2014) Song, I-Wen; Li, Wei-Ru; Chen, Li-Ying; Shen, Li-Fen; Liu, Kai-Ming; Yen, Jeffrey JY; Chen, Yi-Ju; Chen, Yu-Ju; Kraus, Virginia Byers; Wu, Jer-Yuarn; Lee, MT Michael; Chen, Yuan-TsongZDHHC13 is a member of DHHC-containing palmitoyl acyltransferases (PATs) family of enzymes. It functions by post-translationally adding 16-carbon palmitate to proteins through a thioester linkage. We have previously shown that mice carrying a recessive Zdhhc13 nonsense mutation causing a Zdhcc13 deficiency develop alopecia, amyloidosis and osteoporosis. Our goal was to investigate the pathogenic mechanism of osteoporosis in the context of this mutation in mice. Body size, skeletal structure and trabecular bone were similar in Zdhhc13 WT and mutant mice at birth. Growth retardation and delayed secondary ossification center formation were first observed at day 10 and at 4 weeks of age, disorganization in growth plate structure and osteoporosis became evident in mutant mice. Serial microCT from 4-20 week-olds revealed that Zdhhc13 mutant mice had reduced bone mineral density. Through co-immunoprecipitation and acyl-biotin exchange, MT1-MMP was identified as a direct substrate of ZDHHC13. In cells, reduction of MT1-MMP palmitoylation affected its subcellular distribution and was associated with decreased VEGF and osteocalcin expression in chondrocytes and osteoblasts. In Zdhhc13 mutant mice epiphysis where MT1-MMP was under palmitoylated, VEGF in hypertrophic chondrocytes and osteocalcin at the cartilage-bone interface were reduced based on immunohistochemical analyses. Our results suggest that Zdhhc13 is a novel regulator of postnatal skeletal development and bone mass acquisition. To our knowledge, these are the first data to suggest that ZDHHC13-mediated MT1-MMP palmitoylation is a key modulator of bone homeostasis. These data may provide novel insights into the role of palmitoylation in the pathogenesis of human osteoporosis.Item Open Access Psychometric properties of the osteoporosis assessment questionnaire (OPAQ) 2.0: results from the multiple outcomes of raloxifene evaluation (MORE) study.(BMC musculoskeletal disorders, 2014-01) Shen, Wei; Burge, Russel; Naegeli, April N; Shih, Jeremy; Alam, Jahangir; Gold, Deborah T; Silverman, StuartBACKGROUND: We explored psychometric properties of the Osteoporosis Assessment Questionnaire 2.0 in terms of reliability, validity, and responsiveness with generic, clinical, demographic, and preference-based data collected from a population of postmenopausal women with osteoporosis. METHODS: The Multiple Outcomes of Raloxifene Evaluation study was a randomized, placebo-controlled, multinational clinical trial evaluating efficacy and safety of raloxifene. The Osteoporosis Assessment Questionnaire 2.0, a generic quality of life measure (Nottingham Health Profile), and a preference-based measure (Health Utilities Index) were administered at baseline and annually. Psychometric properties of the 14 Osteoporosis Assessment Questionnaire 2.0 domains were evaluated by standard statistical techniques. RESULTS: This study included a subset of 1477 women from the Multiple Outcomes of Raloxifene Evaluation study population completing the questionnaires. Mean (standard deviation) age was 68.4 (6.8) years. Prevalent vertebral fractures were found in 70% (n =1038) of women. Internal consistency was >0.7 in 9 Osteoporosis Assessment Questionnaire 2.0 domains. Correlations were moderate and significant for similar Osteoporosis Assessment Questionnaire 2.0 domain scores, Nottingham Health Profile domains, and Health Utilities Index scores. All but 2 Osteoporosis Assessment Questionnaire 2.0 domains distinguished between patients with or without prevalent vertebral fractures and detected worsening with increased number of vertebral fractures. Women with ≥ 1 incident vertebral fracture generally had a greater worsening in Osteoporosis Assessment Questionnaire 2.0 scores (excluding social activity and support of family and friends) from baseline to study endpoint compared with women without incident vertebral fractures. CONCLUSIONS: Most domains in the Osteoporosis Assessment Questionnaire 2.0 demonstrated robust psychometric properties; however, several domains not showing these criteria may need to be reassessed and removed for a potentially shorter and validated version of the Osteoporosis Assessment Questionnaire.Item Open Access The assessment of bone mineral content and density of the lumbar spine and proximal femur in US submariners.(Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2014-09) Gasier, HG; Hughes, LM; Young, CR; Richardson, AMUnlabelled
The submarine environment is unique in that there is limited space and no sunlight, which may negatively affect skeletal health and lead to accelerated bone loss, osteoporosis, and fractures.Introduction
The primary purpose of this study was to determine whether there was an association with submarine service, specifically time spent at sea, and bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine and dual proximal femur (total hip and femoral neck) measured by DXA.Methods
This is a cross-sectional study of 462 submariners 20-91 years old. Variables included in the analysis were age, height, race, alcohol intake, tobacco use, fracture history, conditions, and medications known to cause bone loss and osteoporosis and submarine service.Results
Of the submarine service predictors, only serving onboard a diesel submarine was determined to be independently associated with a reduction in BMD of the total hip and femur neck, while no submarine service predictor increased the odds of having low BMD. In submariners 50+ years old, the age-adjusted prevalence of osteopenia was 15.7 % (lumbar spine) and 40.4 % (femur neck), while the prevalence of osteoporosis was 4.8 % (lumbar spine) and 4.2 % (femur neck), rates that did not differ from NHANES 2005-2008. In submariners <50 years old, 3.1 % was below the expected range for age. The proportion of submariners 50+ years old that met the FRAX criteria for pharmacological treatment was 12 %.Conclusions
Intermittent periods of submergence that can range from a few days to 3+ months do not appear to compromise skeletal health differently than the general population.