The effects of mitochondrial dysfunction on bone density, osteoblasts and osteoclasts

Abstract

The pathogenesis of falling bone mineral density as a universal feature of advancing age is not fully understood. The process, frequently culminating in the development of osteoporosis, leads to diminishing bone strength and increasing risk of fragility fractures. Fragility fractures associated with falling bone mineral density are common worldwide and are associated with high levels of morbidity, mortality and huge costs to healthcare economies. The cause of declining bone mineral density is thought to be multifactorial. With age, humans are known to accumulate somatic mitochondrial DNA mutations but these have not been attributed to having a significant role in the failure of bone homeostasis. Compelling evidence provided by mouse models suggests somatic mitochondrial DNA mutations may be integral to the ageing process and the associated dysfunction of various other cell types. I have utilised the PolgAmut/mut mitochondrial ‘mutator’ mouse model to study the effects of an increased rate of accumulating mitochondrial DNA mutations and consequent respiratory chain dysfunction on bone density and the functional capacity of osteoblasts and osteoclasts. The aim of this research was to understand the effects of mitochondrial dysfunction on bone biology and its potential role in the pathogenesis of osteoporosis. The research demonstrates that the mitochondrial respiratory chain dysfunction encountered in PolgAmut/mut osteoblasts and osteoclasts is associated with significantly accelerated loss of bone density, reduced functional capacity of osteoblasts to perform mineralisation in vitro, and reduced differentiation and activity of osteoclasts. Exercise was found to have no significantly beneficial effect on PolgAmut/mut osteoblast and whole bone phenotype. Based on these findings, it is possible that accumulating mitochondrial mutations in human ageing have significantly detrimental effects on bone biology and bone mineral density.