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.

mtDNA variability determines spontaneous joint aging damage in a conplastic mouse model

“…We did not detect significant differences in mice at 25 and 75 weeks of age ( Supplementary Figure 4 ). These results are in accordance with our data on the surgically induced OA in the conplastic (BL/6 NZB ) mice and the original strain, where we did not observe differences between sham groups at 25 weeks of age [ 27 ]. Thus, at the basal time (25 weeks), there were no differences between the strains and only when aging progressed did we observe how different mtDNA variants influence the expression of senescence markers predisposing the mice to a worse disease outcome.…”

“…Besides, we analyzed the presence of histopathological changes in synovial tissue and subchondral bone ( Supplementary Figure 2 ). Although we previously detected that conplastic (BL/6 NZB ) mice under a surgically-induced model of OA presented lower damage in these tissues than observed in an original strain BL/6 C57 [ 27 ], in this study we failed to observed any significant difference between both strains in term of pathological changes in these articular tissues. It could be due to the fact that age-related spontaneous model of OA performed in this study is less aggressive and generally causes a lower articular damage.…”

“…Specifically, the medial compartment and the medial femoral condyle were the joint regions where we found significant differences between conplastic (BL/6 NZB ) mice and the original strain BL/6 C57 ( Table 1 ), in accordance with the development of aging damage in human knee. Notably, we observed localized fibrillation and decreased chondrocyte density, but we did not find complete loss of cartilage typical of the OA process, which we observed in a model of surgically induced OA [ 27 ]. These findings on Mankin score levels reveal that mtDNA manipulation can attenuate the aging-related changes that affect the cartilage at joints, reducing their potential contribution to the development of OA.…”

“…Thus, our results confirmed that there were no basal differences between the two strains and that these differences appeared only in old age. Moreover, in our previous study using a model of surgically induced OA, we observed that conplastic (BL/6 NZB ) mice also presented more cartilage expression of LC3 and Beclin-1 than the original strain [ 27 ]. In order to confirm that increment of LC3 and Beclin-1 proteins reflected an augmentation of autophagy flux, we analyzed p62 levels, a classical receptor and indicator of autophagy activity as P62 accumulates when autophagy is inhibited, and decreased levels can be observed when autophagy is elicited [ 2 ].…”

Genetic biomarkers in osteoarthritis: a quick overview

“…In the field of OA, the use of these animals demonstrated the functional impact of non-pathological variants of mtDNA on OA process using a surgically induced OA model. The latter study demonstrated that specific conplastic mice BL/6 NZB developed less severe OA, as indicated by a reduced Osteoarthritis Research Society International (OARSI) histopathology score and synovitis, accompanied by higher autophagy and lower apoptosis 55 .…”