Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium. We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging. Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance. Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.

中文翻译：

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遗传多样性 UM-HET3 小鼠衰老过程中原发性骨关节炎的发展


原发性骨关节炎 (OA) 的发生没有可识别的根本原因，例如先前受伤或特定的医疗状况。年龄是骨关节炎的一个主要影响因素，随着年龄的增长，各种关节组织逐渐发生变化，包括关节软骨退化、软骨下骨（SCB）形态改变和滑膜炎症。我们调查了老年遗传多样性 UM-HET3 小鼠中原发性 OA 的患病率。分别使用国际骨关节炎研究协会 (OARSI) 评分系统和微型 CT 评估 182 个 22-25 个月大小鼠膝关节的关节软骨 (AC) 完整性和 SCB 形态。此外，我们还探讨了亚甲蓝 (MB) 和线粒体醌 (MitoQ) 这两种影响线粒体功能的药物对衰老过程中 OA 患病率和进展的影响。老年 UM-HET3 小鼠在两性中均表现出原发性 OA 的高患病率。研究发现，两性的累积 AC (cAC) 评分与滑膜炎以及雌性小鼠的骨赘形成之间存在显着的正相关性。异位软骨形成与 cAC 评分没有显着相关性。在两性中，AC 评分与软骨细胞炎症标志物（包括基质金属蛋白酶 13、诱导型一氧化氮合酶和含有 Pyrin 结构域的 NLR 家族 3 炎症体）之间存在显着的直接相关性，表明 OA 严重程度与炎症之间存在联系。此外，细胞周期停滞的标记物，例如 p16 和 β-半乳糖苷酶，也与 AC 评分相关。在雄性小鼠中，SCB形态特征与cAC评分之间没有发现显着相关性，而在雌性小鼠中，cAC评分与胫骨SCB板骨密度之间存在显着相关性。 值得注意的是，MB 和 MitoQ 治疗以性别特异性方式影响疾病的进展。 MB治疗显着降低了膝关节内侧的cAC评分，而MitoQ治疗降低了cAC评分，但这些并没有达到显着性。我们的研究提供了对老年 UM-HET3 小鼠原发性 OA 患病率和进展的全面见解，强调了 MB 和 MitoQ 治疗的性别特异性效应。 AC 评分与各种病理因素之间的相关性强调了 OA 的多方面性质及其与炎症和软骨下骨变化的关联。