Research Paper Advance Articles
mtDNA variability determines spontaneous joint aging damage in a conplastic mouse model
- 1 Unidad de Genómica, Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña 15006, Spain
- 2 Universidade da Coruña (UDC), Grupo de Investigación de Reumatología y Salud (GIR-S), Departamento de Biología, Campus de Zapateria, A Coruña 15011, Spain
- 3 Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain
- 4 CIBERES: C/ Melchor Fernández-Almagro 3, Madrid 28029, Spain
- 5 Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, UK
- 6 Centro Tecnológico de Formación Xerencia de Xestión Integrada A Coruña (XXIAC), A Coruña 15006, Spain
- 7 Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid 28029, Spain
- 8 Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, C/ Melchor Fernández-Almagro 3, Madrid 28029, Spain
- 9 Universidade da Coruña (UDC), Grupo de Investigación de Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Campus de Oza, A Coruña 15008, Spain
Received: October 20, 2021 Accepted: June 14, 2022 Published: July 2, 2022https://doi.org/10.18632/aging.204153
How to Cite
Copyright: © 2022 Scotece et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Mitochondria and mtDNA variations contribute to specific aspects of the aging process. Here, we aimed to investigate the influence of mtDNA variation on joint damage in a model of aging using conplastic mice. A conplastic (BL/6NZB) mouse strain was developed with the C57BL/6JOlaHsd nuclear genome and NZB/OlaHsd mtDNA, for comparison with the original C57BL/6JOlaHsd strain (BL/6C57). Conplastic (BL/6NZB) and BL/6C57 mice were sacrificed at 25, 75, and 90 weeks of age. Hind knee joints were processed for histological analysis and joint pathology graded using the Mankin scoring system. By immunohistochemistry, cartilage expression of markers of autophagy (LC3, Beclin-1, and P62) and markers of senescence (MMP13, beta-Galactosidase, and p16) and proliferation (Ki67) were analyzed. We also measured the expression of 8-oxo-dG and cleaved caspase-3.
Conplastic (BL/6NZB) mice presented lower Mankin scores at 25, 75, and 90 weeks of age, higher expression of LC3 and Beclin-1 and lower of P62 in cartilage than the original strain. Moreover, the downregulation of MMP13, beta-Galactosidase, and p16 was detected in cartilage from conplastic (BL/6NZB) mice, whereas higher Ki67 levels were detected in these mice. Finally, control BL/6C57 mice showed higher cartilage expression of 8-oxo-dG and cleaved caspase-3 than conplastic (BL/6NZB) mice. This study demonstrates that mtDNA genetic manipulation ameliorates joint aging damage in a conplastic mouse model, suggesting that mtDNA variability is a prognostic factor for aging-related osteoarthritis (OA) and that modulation of mitochondrial oxidative phosphorylation (OXPHOS) could be a novel therapeutic target for treating OA associated with aging.