Mitochondrial DNA Impact on Joint Damaged Process in a Conplastic Mouse Model After Being Surgically Induced With Osteoarthritis

[Abstract] It has been suggested that mitochondrial dysfunction and mtDNA variations may contribute to osteoarthritis (OA) pathogenesis. However, the causative link to support this claim is lacking. Here, we surgically-induced OA in conplastic mice in order to evaluate the functional consequences of mtDNA haplotypes in their joint degeneration. BL/6NZB strain was developed with C57BL/6JOlaHsd nuclear genome and NZB/OlaHsdmtDNA while BL/6C57, which is the original, was developed with C57BL/6JOlaHsd nuclear genome and C57/OlaHsdmtDNA for comparison. The surgical DMM OA model was induced in both strains. Their knees were processed and examined for histopathological changes. Cartilage expression of markers of autophagy, apoptosis, oxidative stress and senescence were also analyzed by immunohistochemistry. The joints of BL/6NZB mice that were operated presented more cellularity together with a reduced OARSI histopathology score, subchondral bone, menisci score and synovitis compared to those of BL/6C57 mice. This was accompanied with higher autophagy and a lower apoptosis in the cartilage of BL/6NZB mice that were operated. Therefore, the study demonstrates the functional impact of non-pathological variants of mtDNA on OA process using a surgically-induced OA model. Conplastic (BL/6NZB ) mice develop less severe OA compared to the BL/6C57original strain. These findings demonstrate that mitochondria and mtDNA are critical targets for potential novel therapeutic approaches to treat osteoarthritis.This work is supported by grants from Fondo de Investigación Sanitaria (CIBERCB06/01/0040-Spain, RETIC-RIER-RD16/0012/0002, PI16/02124, PI19/01206) integrated in the National Plan for Scientific Program, Development and Technological Innovation 2013–2016 and funded by the ISCIII-General Sub direction of Assessment and Promotion of Research-European Regional Development Fund (FEDER)“A way of making Europe”. MS is “Sara Borrell” researcher funded by ISCIII and FEDER (CD16/00099). IRP is funded by the Instituto de Salud Carlos III through a Miguel Servet-II programme (CPII17/00026). CVG is supported by Contrato Posdoctoral Xunta de Galicia (ED481D2017/023)