Background/Purpose:

Accumulated data indicated that osteoarthritis has a strong genetic component with a prevalent role of mitochondria and mtDNA variations. In the present work, we aimed to study the influence of the mtDNA variation in the joint deterioration in aging-related and surgically-induced OA in mice with the same nuclear genome but different mtDNA variants (named conplastic mice).

Methods: Conplastic mice (BL/6^NZB) strain was developed with the C57BL/6JOlaHsd nuclear genome and the NZB/OlaHsd mtDNA to compare with the original C57BL/6JOlaHsd strain (BL/6^C57).

In the spontaneous aging-related OA model, mice were kept under normal conditions and sacrificed at 25, 75 and 90 weeks of age. Hind knee joints from BL/6^NZB mice as well as from BL/6^C57 mice were processed and cut into coronal sections for histological analysis. All sections were stained with Hematoxylin-Eosine and Safranin O-fast green and graded using a Mankin scoring system. Cartilage expression of markers of autophagy like LC3 and metalloproteinases like MMP-13 were also analyzed by immunohistochemistry. The surgical OA model was induced in 17 months old BL/6^C57 and BL/6^NZB mice by transection of the medial meniscotibial ligament (DMM model) of the hind left knee joint. The right knee joint was used as sham surgery. The animals were euthanized 8 weeks later. Both hind knees were processed and cut into sagittal sections and examined for histopathological changes (OARSI scoring system, subchondral bone changes).

Results: In the aging model, conplastic mice BL/6^NZB presented reduced cartilage Mankin score at 25 (p=0.0317), 75 (p=0.0087) and 90 (p=0.0484) weeks compared with mice of the original strain BL/6^C57 at the same age. Specifically, we showed a reduced score in both femoral condyle (FC) and tibial plateau (TP) of BL/6^NZB mice that reached the statistical significance at 25 (FC: p=0.0317; TP: p=0.0079) and 75 weeks (FC: p=0.0411; TP: p=0.0238). These results were accompanied with more expression of LC3 in cartilage from BL/6^NZB mice at 75 and 90 weeks when compared with cartilage from BL/6^C57 at the same age. Difference in MMP13 cartilage expression between the two mice strains were also found.  In the surgical OA model, we found that joints from BL/6^NZB mice presented a reduced OARSI score compared with BL/6^C57 (p=0.018) in both femoral condyle and tibial plateau. We also observed less subchondral bone changes in BL/6^NZB mice compared with BL/6^C57 mice (p=0.035).

Conclusion: This study demonstrates that mtDNA genetic manipulation improve both spontaneous joint aging and joint degradation in a conplastic aging animal model and in a surgically-induced OA conplastic mice respectively. BL/6^NZB conplastic mice develop less severe spontaneous joint aging and OA compared with the original strain BL/6^C57. These results support the hypothesis that mtDNA background has a role in the process of joint damage, suggesting a potential role of mtDNA as a novel therapeutic target in OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mitochondrial-dna-impact-on-joint-degeneration-process-using-dmm-oa-and-spontaneous-aging-conplastic-mice-models/