Cargando…

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

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 effect...

Descripción completa

Detalles Bibliográficos
Autores principales: Dobson, Philip F., Dennis, Ella P., Hipps, Daniel, Reeve, Amy, Laude, Alex, Bradshaw, Carla, Stamp, Craig, Smith, Anna, Deehan, David J., Turnbull, Doug M., Greaves, Laura C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363892/
https://www.ncbi.nlm.nih.gov/pubmed/32669663
http://dx.doi.org/10.1038/s41598-020-68566-2
_version_ 1783559731759022080
author Dobson, Philip F.
Dennis, Ella P.
Hipps, Daniel
Reeve, Amy
Laude, Alex
Bradshaw, Carla
Stamp, Craig
Smith, Anna
Deehan, David J.
Turnbull, Doug M.
Greaves, Laura C.
author_facet Dobson, Philip F.
Dennis, Ella P.
Hipps, Daniel
Reeve, Amy
Laude, Alex
Bradshaw, Carla
Stamp, Craig
Smith, Anna
Deehan, David J.
Turnbull, Doug M.
Greaves, Laura C.
author_sort Dobson, Philip F.
collection PubMed
description 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 PolgA(mut/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 PolgA(mut/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 PolgA(mut/mut) mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgA(mut/mut) cells. Finally, application of an exercise intervention to a subset of PolgA(mut/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.
format Online
Article
Text
id pubmed-7363892
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-73638922020-07-17 Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss Dobson, Philip F. Dennis, Ella P. Hipps, Daniel Reeve, Amy Laude, Alex Bradshaw, Carla Stamp, Craig Smith, Anna Deehan, David J. Turnbull, Doug M. Greaves, Laura C. Sci Rep Article 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 PolgA(mut/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 PolgA(mut/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 PolgA(mut/mut) mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgA(mut/mut) cells. Finally, application of an exercise intervention to a subset of PolgA(mut/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. Nature Publishing Group UK 2020-07-15 /pmc/articles/PMC7363892/ /pubmed/32669663 http://dx.doi.org/10.1038/s41598-020-68566-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dobson, Philip F.
Dennis, Ella P.
Hipps, Daniel
Reeve, Amy
Laude, Alex
Bradshaw, Carla
Stamp, Craig
Smith, Anna
Deehan, David J.
Turnbull, Doug M.
Greaves, Laura C.
Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
title Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
title_full Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
title_fullStr Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
title_full_unstemmed Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
title_short Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
title_sort mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363892/
https://www.ncbi.nlm.nih.gov/pubmed/32669663
http://dx.doi.org/10.1038/s41598-020-68566-2
work_keys_str_mv AT dobsonphilipf mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT dennisellap mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT hippsdaniel mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT reeveamy mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT laudealex mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT bradshawcarla mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT stampcraig mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT smithanna mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT deehandavidj mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT turnbulldougm mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss
AT greaveslaurac mitochondrialdysfunctionimpairsosteogenesisincreasesosteoclastactivityandacceleratesagerelatedboneloss