FRI0522 MITOCHONDRIAL BACKGROUND IMPACT ON THE JOINT DEGENERATION PROCESS DURING AGING AND FORCED EXERCISE: A CONPLASTIC MOUSE MODEL
Authors: Morena Scotece, Ignacio Rego-Perez, Ana Victoria Lechuga Vieco, Purificación Filgueira-Fernández, Jose Antonio Enriquez, Francisco J. Blanco
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Several studies indicated that osteoarthritis has a strong genetic component with a prevalent role of mitochondria and mtDNA variations (1). <h3>Objectives</h3> In the present study, we aimed to investigated the influence of the mtDNA variation in the joint deterioration using mice with the same nuclear genome but different mtDNA variants (named conplastic mice) (2) during aging and forced exercise. <h3>Methods</h3> Conplastic mice (BL/6<sup>NZB</sup>) strain was developed with the C57BL/6JOlaHsd nuclear genome and the NZB/OlaHsd mtDNA to compare with the original C57BL/6JOlaHsd strain (BL/6<sup>C57</sup>). Knee joints from BL/6<sup>NZB</sup> mice as well as from BL/6<sup>C57</sup> mice were processed and cut into coronal sections. The mice were sacrificed at 25, 75 and 90 weeks of age and knee joints were collected for histological analysis. All sections were stained with Hematoxylin-Eosine and Safranin O-fast green and graded using a Mankin scoring system. Another group of mice from both BL/6<sup>NZB</sup> and BL/6<sup>C57</sup> strains were subjected to exercise by running in a treadmill 400m/day three times a week. After 75 and 90 weeks of age, mice were sacrificed and knee joints were processed for histological analysis. Cartilage expression of markers of autophagy like LC3 and metalloproteinases like MMP-13 were also analysed by immunohistochemistry in both strains. The results are given as mean ± SEM and statistical analysis was performed using non parametric unpaired t-test (Graph Pad Prism v 6.0). <h3>Results</h3> In response to aging, conplastic mice BL/6<sup>NZB</sup> presented reduced cartilage Mankin score at 25 (p=0.0079), 75 (p=0.0087) and 90 (p=0.064) weeks when compared with mice of the original strain BL/6<sup>C57</sup> at the same age. Specifically, we showed a reduced score in both femoral condyle (FC) and tibial plateau (TP) of BL/6<sup>NZB</sup> mice that reached the statistical significance at 25 (FC: p=0.0317; TP: p=0.0079), 75 (FC: p=0.0411; TP: p=0.0238) and borderline the statistical significance at 90 (FC: p=0.0649; TP: p=0.0628) weeks of age. These results were accompanied with more expression of LC3 in cartilage from BL/6<sup>NZB</sup> mice at 75 weeks when compared with cartilage from BL/6<sup>C57</sup> at the same age (p=0.0152). We also reported a significant decrease of LC3 expression in cartilage from mice at 75 weeks when compared with mice at 25 weeks in both strains confirming the decrease of autophagy with aging. Difference in MMP13 cartilage expression between the two mice strains were also found. In the mice subjected to exercise, BL/6<sup>C57</sup> presented an increased cartilage score in the medial compartment (p=0.0286) and lateral compartment (p=0.057) of the joint at 90 weeks when compared with BL/6<sup>NZB</sup> mice at the same age. <h3>Conclusion</h3> This study demonstrated that aging and forced exercise in conplastic mice BL/6<sup>NZB</sup> are associated with a reduced joint deterioration compared with the original strain BL/6<sup>C57</sup>. Moreover, we showed that mtDNA variants can improve the aging process at joint level through the modulation of autophagy. These results support the hypothesis that mtDNA background has a role in the process of joint damage, suggesting that mtDNA has potential as novel therapeutic target in OA associated to aging. <h3>References</h3> [1] Mitochondrial DNA variation and the pathogenesis of osteoarthritis phenotypes. Nat Rev Rheumatol. 2018Jun;14(6):327-340 [2] Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing; Latorre-Pellicer, et al. Nature2016;535(7613):561–5 <h3>Disclosure of Interests</h3> Morena Scotece: None declared, Ignacio Rego-Perez: None declared, Ana Victoria Lechuga Vieco: None declared, Purificación Filgueira-Fernández : None declared, Jose Antonio Enriquez: None declared, Francisco J. Blanco Consultant for: AbbVie, Bioiberica, BMS, GSK, Grünenthal, Janssen, Lilly, Pfizer, Regeneron, Roche, Sanofi, TRB Chemedica, and UCB