Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss

Philip F Dobson,Amy Reeve,Daniel Hipps,Laura C Greaves,Carla Bradshaw,Anna Smith,Craig Stamp,David J Deehan,Doug M Turnbull,Alex Laude,Ella P Dennis

doi:10.1038/s41598-020-68566-2

Abstract

The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgAmut/mut mitochondrial DNA ‘mutator’ mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgAmut/mut mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgAmut/mut mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgAmut/mut cells. Finally, application of an exercise intervention to a subset of PolgAmut/mut mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.

Highlights

The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood
We have demonstrated that osteoblasts[44] osteoclast accumulate mitochondrial defects occur within ageing wild type mice and at an accelerated rate in PolgAmut/mut mice, and that these findings correspond to increased bone loss, reduced bone formation rate, reduced osteoblast population density, and increased osteoclast population density in vivo
With micro computed tomography (CT) scanning, we found a significant reduction in lumbar vertebral bone volume (BV)/tissue volume (TV) in male PolgAmut/mut mice as young as 4 months and by 7 months in female PolgAmut/mut mice

Summary

Introduction

The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgAmut/mut mitochondrial DNA ‘mutator’ mouse. Intracellular changes within bone tissue that occur with age, accumulating mitochondrial DNA (mtDNA) mutations, may play a significant role in the failure of bone homeostasis leading to declining BMD levels. The PolgAmut/mut mitochondrial ‘mutator’ mouse possesses a defective version of the only proof reading domain of mtDNA polymerase[36] which causes it to accumulate mitochondrial DNA point mutations at 3–5 times the rate of wild type mice resulting in a premature ageing phenotype, making it an excellent mouse model of ageing[37]. Mice with global and osteocyte specific knockdown of superoxide dismutase (Sod2), an enzyme which protects against mitochondrial oxidative stress, develop osteoporosis prematurely[39]

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