Dr. David Hoey

Summary

Every 3 seconds a person suffers an osteoporosis-related bone fracture, resulting in significant morbidity, mortality, and health-care costs. Osteoporosis arises when there is an imbalance between resorption and formation resulting in net bone loss. Current therapeutics are limited in efficacy and by side-effects. A potent regulator of bone formation and repair is physical loading. Bone cells sense mechanical stimuli and subsequently coordinate net bone gain by secreting multitargeted paracrine factors. Recent findings by the applicant indicates that these factors are delivered via extracellular vesicles (EV), which are membrane-bound cargoes that facilitate cell-cell communication. Therefore, this research aims to develop a novel EV-based multitargeted therapy that mimics the beneficial effects of physical exercise, by inhibiting osteoclastogenesis and bone resorption, while also enhancing angiogenesis, osteogenesis and bone formation. The identification of EVs and associated components as central to loading-induced bone anabolism will lead to the direct manipulation of multiple cell types via mechanically-activated EV based therapeutics. These therapeutics would therefore be used as a novel multitargeted strategy to treat osteoporosis. Furthermore, these EVs will be incorporated into scaffolds, generating innovative mechanobiomimetic materials for bone regeneration. These therapies have the potential to transform how millions suffering from osteoporosis and bone defects are treated.

Funding Agency

Science Foundation Ireland

Programme

Frontiers for the Future

Summary

This project will combine expertise within the applicant's team, along with collaborators in the University of Birmingham, to develop new materials and cell culture platforms which will facilitate the recapitulation of human bone physiology in a dish, focusing on the establishment of a human osteocyte network within a vascularised and mineralised tissue that is capable of undergoing remodelling, in response to both hormonal and physical cues. This first of its kind platform will then be used to screen novel therapeutics which are being developed by the applicant in the form of extracellular vesicles (EVs) and G-protein coupled receptors (Gpr161) as treatments for osteoporosis and will compare against commercial standards.

Funding Agency

Trinity College Dublin

Programme

Provosts PhD Award

Summary

Spinal fusion is a surgical procedure whereby two or more vertebrae are joined together to grow into a single solid bone. Indications for fusion procedures include fractured vertebrae, tumour resection and degenerative spinal conditions. The incidence of spinal fusion surgery is rising dramatically worldwide, in part due to an ever increasing aging population. In the setting of osteoporosis, which is also linked to aging, spinal fusion is associated with significant technical challenges, morbidity and healthcare costs. More than 200 million people are suffering from osteoporosis worldwide. Insufficiency fractures, failure of fusion and instrumentation failure are some of the complications encountered. Furthermore, the revision surgery required to address these complications is a major surgical undertaking associated with significant risk and long-term functional restrictions. Our hypothesis is that the increased incidence of complications is secondary to a defective stem cell population, and this may be therapeutically addressed through the use of novel bioprinted materials. We will first track the stem cell contributions to spinal fusion using a transgenic mouse model and compare how this is altered in an induced osteoporotic model (Workpackage 1). In workpackage 2 we will characterise stem cells isolated from osteoporotic and non-osteoporotic patients undergoing spinal fusion surgery. We will compare the regenerative potential of these cells to patient spinal fusion outcomes with the hypothesis that those patients with poor fusion outcomes will correlate with the quality of stem cells. Finally, we will attempt to use novel bioprinted materials previously optimised to enhance stem cell based bone formation to increase spinal fusion rates in the mouse model described earlier. Therefore this project will identify stem cells as critical to spinal fusion success and will demonstrate the applicability of novel materials to target this cell to enhance fusion in osteoporosis addressing the currently unacceptable high failure rates of this procedure.

Funding Agency

Irish Research Council

Programme

Government of Ireland Postgraduate Scholarship

Summary

Every 30 seconds a person suffers an osteoporosis-related bone fracture in the EU, resulting in significant morbidity, mortality, and health-care costs estimated at €36 billion annually. Current therapeutics target bone resorbing osteoclasts, but these are associated with severe side effects. Osteoporosis arises when mesenchymal stem cells (MSC) fail to produce sufficient numbers of bone forming osteoblasts. A key regulator of MSC behaviour is physical loading, yet the mechanisms by which MSCs sense and respond to changes in their mechanical environment are virtually unknown. Primary cilia are nearly ubiquitous 'antennae-like' cellular organelles that have very recently emerged as extracellular mechano/chemo-sensors and thus, are strong candidates to play an important role in regulating MSC responses in bone. However, to date, research on the stem cell primary cilium is almost non-existent. Therefore, the objective of this research program is to determine the role of the understudied primary cilium and associated molecular components in the osteogenic differentiation and recruitment of human MSCs in loading-induced bone adaptation. This will be achieved through ground breaking in vitro and in vivo techniques developed by the applicant. The knowledge generated in this proposal will represent a profound advance in our understanding of stem cell mechanobiology. In particular, the identification of the cilium and associated molecules as central to stem cell behaviour will lead to the direct manipulation of MSCs via novel cilia-targeted therapeutics that mimic the regenerative influence of loading at a molecular level. These novel therapeutics would therefore target bone formation rather than resorption, providing an innovative alternative path to treatment, resulting in an improved supply of bone forming cells, preventing osteoporosis. Furthermore, these novel therapeutics will be incorporated into biomaterials generating novel bioactive osteoinductive scaffolds. These advances will not only improve quality of life for the patient but will significantly reduce the financial burden of bone loss diseases in the EU.

Funding Agency

European Research Council

Programme

Starting Grant

Summary

Every 30 seconds a person suffers an osteoporosis-related bone fracture, resulting in significant morbidity, mortality, and health-care costs estimated at 36billion euro annually. Current therapeutics target osteoclasts but are associated with severe side effects. Osteoporosis arises when stem cells (MSCs) fail to produce sufficient numbers of osteoblasts. A key regulator of MSC behaviour is loading, yet the mechanisms by which MSCs proliferate, differentiate and are recruited to sites of loading to replace exhausted osteoblasts remain elusive. Osteocytes are ideally numbered and positioned to be sensors and regulators of bone formation. However research on osteocyte-MSC signalling is almost non-existent. Therefore the objective of this research project is to determine the role of the osteocyte and associated signalling mechanisms in regulating MSC contributions to bone formation and to develop novel 'Bone-on-a-Chip' microfluidic platforms for the validation of novel anabolic therapeutics for osteoporosis.

Funding Agency

Irish Research Council

Programme

Postgraduate Scholarship