Article
Increased reactive oxygen species in osteoblast progenitor cells lead to age-related bone loss in mice
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Authors
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Xiangxu Chen
- Institut für Unfallchirurgische Forschung und Biomechanik, Zentrum für Traumaforschung (ZTF) Ulm, Universität Ulm, Ulm, Germany
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Anna Vikman
- Institut für Unfallchirurgische Forschung und Biomechanik, Zentrum für Traumaforschung (ZTF) Ulm, Universität Ulm, Ulm, Germany
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Melanie Haffner-Luntzer
- Institut für Unfallchirurgische Forschung und Biomechanik, Zentrum für Traumaforschung (ZTF) Ulm, Universität Ulm, Ulm, Germany
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Verena Fischer
- Institut für Unfallchirurgische Forschung und Biomechanik, Zentrum für Traumaforschung (ZTF) Ulm, Universität Ulm, Ulm, Germany
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Jan Tuckermann
- Institut für Molekulare Endokrinologie der Tiere, Universität Ulm, Ulm, Germany
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Karin Scharffetter-Kochanek
- Dermatologie und Allergologie, Universität Ulm, Ulm, Germany
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Anita Ignatius
- Institut für Unfallchirurgische Forschung und Biomechanik, Zentrum für Traumaforschung (ZTF) Ulm, Universität Ulm, Ulm, Germany
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Astrid Liedert
- Institut für Unfallchirurgische Forschung und Biomechanik, Zentrum für Traumaforschung (ZTF) Ulm, Universität Ulm, Ulm, Germany
| Published: | October 22, 2019 |
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Outline
Text
Objectives: Reactive oxygen species (ROS) mainly arise during cellular respiration in the mitochondria and are eliminated in the young organism by antioxidant defense mechanisms, including the mitochondrial enzyme superoxide dismutase (SOD)2. ROS concentration in the bone increases with age and with estrogen deficiency, as the activity of antioxidant defense mechanisms decreases. It has been shown that aging of human osteoblast progenitor cells is accompanied by decreased activity of SOD2 and increased production of ROS [1]. Therefore, the aim of this study was to investigate the influence of osteoblast-specific Sod2 deficiency on bone mass in mice.
Methods: Female Runx2CreSod2fl/fl and Runx2CreSod2-/- were sacrificed at the age of 12 and 52 weeks. Femora were assessed by micro-computed tomography and histomorphometrically. Bone cryosections and osteoblast progenitor cells isolated from the long bones were used to analyse levels of ROS with dihydroethidium. Osteoblast progenitor cells were evaluated for their proliferation rate and differentiation potential by BrdU assay and cytochemical stainings. Expression analysis and senescence-associated b-galactosidase staining were used to assess cell senescence of osteoblast progenitor cells. Statistics: t-test, p< 0.05.
Results and conclusion: Femura of Runx2CreSod2-/- mice compared with femura of Runx2CreSod2fl/f mice showed a significantly reduced trabecular bone volume fraction, a decreased trabecular number, an increased trabecular separation as well as a decreased cortical thickness and cortical tissue mineral density. Additionally, we detected a reduced number of osteoblasts and an increased number of osteoclasts. The bone of Runx2CreSod2-/- mice were characterised by higher levels of ROS as well as higher expression of senescence-associated biomarkers, including p16INK4a and FOXO3a. Osteoblast progenitor cells from Runx2CreSod2-/- mice showed a lower proliferation rate, a reduced differentiation potential accompanied with an increased activity and expression of senescence-associated biomarkers.
Our study showed that osteoblast-specific Sod2 deficiency leads to age-related bone loss due to an accelerated senescence of osteoblast progenitor cells.
References
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- Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev. 2008 Mar;129(3):163-73. DOI: 10.1016/j.mad.2007.12.002
