PMID- 38343826 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240304 DP - 2024 Jan 22 TI - Development of primary osteoarthritis during aging in genetically diverse UM-HET3 mice. LID - rs.3.rs-3858256 [pii] LID - 10.21203/rs.3.rs-3858256/v1 [doi] AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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 beta-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. CONCLUSIONS: 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. FAU - Poudel, Sher Bahadur AU - Poudel SB AD - David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY. FAU - Ruff, Ryan R AU - Ruff RR AD - David B. Kriser Dental Center, Biostatistics Core, Department of Epidemiology and Health Promotion, New York University College of Dentistry New York, NY 10010-4086. FAU - Yildirim, Gozde AU - Yildirim G AD - David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY. FAU - Miller, Richard A AU - Miller RA AD - Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA. FAU - Harrison, David E AU - Harrison DE AD - The Jackson Laboratory, Bar Harbor, ME, USA. FAU - Strong, Randy AU - Strong R AD - Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies and Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA. FAU - Kirsch, Thorsten AU - Kirsch T AD - Department of Orthopaedic Surgery, NYU Grossman School of Medicine, and Department of Biomedical Engineering, NYU Tandon School of Engineering, New York, NY. FAU - Yakar, Shoshana AU - Yakar S AD - David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY. LA - eng GR - P30 AG038070/AG/NIA NIH HHS/United States GR - S10 OD010751/OD/NIH HHS/United States GR - R01 AG056397/AG/NIA NIH HHS/United States GR - U01 AG022308/AG/NIA NIH HHS/United States GR - U01 AG022303/AG/NIA NIH HHS/United States GR - P30 AG013319/AG/NIA NIH HHS/United States PT - Preprint DEP - 20240122 PL - United States TA - Res Sq JT - Research square JID - 101768035 PMC - PMC10854287 OTO - NOTNLM OT - UM-HET3 OT - antioxidants OT - cartilage OT - methylene blue OT - mitoquinone OT - osteoarthritis OT - sub-chondral bone COIS- Additional Declarations: No competing interests reported. Competing interest: The authors declare no conflict of interest. All authors have discussed the results and approved the final version of the manuscript. SY is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. EDAT- 2024/02/12 15:42 MHDA- 2024/02/12 15:43 PMCR- 2024/02/09 CRDT- 2024/02/12 04:11 PHST- 2024/02/12 15:42 [pubmed] PHST- 2024/02/12 15:43 [medline] PHST- 2024/02/12 04:11 [entrez] PHST- 2024/02/09 00:00 [pmc-release] AID - rs.3.rs-3858256 [pii] AID - 10.21203/rs.3.rs-3858256/v1 [doi] PST - epublish SO - Res Sq [Preprint]. 2024 Jan 22:rs.3.rs-3858256. doi: 10.21203/rs.3.rs-3858256/v1.