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Title: Mitochondrial dysfunction in the pathogenesis of osteoporosis
Authors: Hipps, Daniel
Issue Date: 2021
Publisher: Newcastle University
Abstract: Osteoporosis is a skeletal disease, characterised by reduced bone mass and altered microarchitecture, with subsequent loss of strength, increased fragility and risk of fragility fractures. Hip fractures alone cost the NHS £2 billion per year and have associated high morbidity and mortality. The pathogenesis of falling bone mineral density, ultimately leading to a diagnosis of osteoporosis is incompletely understood but the disease is currently thought to be multifactorial. Humans are known to accumulate mitochondrial mutations with age and mounting evidence suggests that this may be intrinsic to changes in phenotype with advancing age and pathogenesis of age-related disease. Mitochondrial mutations have been shown to occur from the age of 30 years in tissues such as colon, which interestingly correlates with commencement of decline in bone mineral density. This work has demonstrated the presence of mitochondrial DNA mutations in individual human stem cells and respiratory chain deficiency in human osteoblasts for the first time using novel techniques including single-cell PCR, flow cytometry and imaging mass cytometry. Work with the Polgmut/mut mouse model which acquire mitochondrial mutations at an enhanced rate, has demonstrated significantly higher levels of osteoblast respiratory chain deficiency compared to age matched wild type controls. This was associated with significantly reduced osteoblast population densities, reduced bone formation and increased osteoclast activity. Through these novel techniques, this work has demonstrated that underlying mitochondrial pathology directly affects mesenchymal stem cells and osteoblast potentially contributing to osteoporosis which will lead the way for development of new treatment modalities.
Description: Ph. D. Thesis.
Appears in Collections:Institute of Neuroscience

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