The Impact of Mitochondrial Dysfunction on Human Bone Cell Metabolism and Remodelling

Intact mitochondrial activity including adequate energy supplies is vital for metabolic active tissues i.e. skeletal muscle, heart and brain. The human skeleton represent an additional highly metabolically active tissue; nevertheless the significance of the mitochondrial role in human skeletal bone health may be further investigated.

Bone remodelling constitutes the coupled and continuous regenerative process of bone degradation by bone resorbing cells osteoclasts (OC) followed by formation of bone matrix by bone forming osteoblasts (OB). Quantitative imbalance between resorption and formation results in skeletal disorders with low bone mass including osteoporosis, and its increased risk of fragility fractures.

Mitochondria generate cellular energy adenosine triphosphate (ATP) through oxidative phosphorylation process (OXPHOS) in the respiratory chain (RC) with a secondary production of the deleterious by-products free radicals i.e. reactive oxygen species (ROS). Notably, mitochondria hold their own DNA (m.DNA), and RC subunits are encoded by m.DNA and nuclear DNA (n.DNA) genes, respectively. With ageing, deleterious somatic m.DNA mutations accumulate in skeletal muscle and heart, and somatic m.DNA mutations as well as inherited m.DNA or n.DNA mutations may result in mitochondrial dysfunction with impaired ATP production and accumulation of ROS. m.DNA mutations may impair brain, skeletal-, and cardiac muscle function, but the effects on human bone cell metabolism and remodelling are unknown. A recent study of a cohort of young individuals indicates that mitochondrial diseases pose a risk for bone fragility fractures.

Preclinical studies suggest that ATP and ROS regulate bone metabolism. The m.DNA number and mitochondrial activity increase to support differentiation from human skeletal (mesenchymal) stem cells (hMSC) to mature bone forming OBs. Inhibition of mitochondrial activity or increase in ROS levels suppress OB differentiation. Similarly, OCs are rich in mitochondria. Human OC cultures demonstrate that energy supplies for OC differentiation from their progenitors is based on OXPHOS while OC resorption activity relies on glycolysis.

In addition, emerging evidence suggest that metabolic plasticity i.e. regulation of glycolysis, OXPHOS, and pyruvate levels, contribute to regulation of OB and OC differentiation.