Adenosine Delivery to Mitigate Bone Disorders

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2025-09-14

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2023

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Abstract

Bone 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.

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Newman, Hunter (2023). Adenosine Delivery to Mitigate Bone Disorders. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/29102.

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