ObjectiveTo characterize the serum protein profiles of osteoarthritis model mice, particularly mice with early-stage osteoarthritis, using liquid chromatography-mass spectrometry (LC-MS/MS).DesignSerum and knee samples were collected from 5 control mice and 15 osteoarthritis model mice that underwent destabilization of the medial meniscus (DMM). Osteoarthritic knee samples were collected 4, 8, and 12 weeks after DMM. Knee osteoarthritis severity was scored using the Osteoarthritis Research Society International (OARSI) scoring system. All serum samples were analyzed via LC-MS/MS after removing highly abundant proteins using a ProteoMiner kit (Bio-Rad).ResultsThe average OARSI scores of the medial tibial plateau and medial femoral condyle at 8 weeks after DMM (3.40 ± 1.02 points, = 0.03; 2.60 ± 1.71 points, = 0.03) and 12 weeks after DMM (8.30 ± 3.12 points, = 0.03; 4.80 ± 0.75 points, = 0.03) were significantly higher than the corresponding values in the control group. Compared to those in the control model, 15, 35, and 56 proteins showed different expression levels at 4, 8, and 12 weeks after DMM, respectively. Differentially expressed proteins at 4 weeks after DMM included adenylate kinase, type IV intermediate filament protein, nestin, and insulin-like growth factor-binding proteins. The pathways activated at 4 weeks after DMM differed from those activated at 8 and 12 weeks after DMM.ConclusionProtein expression and activation pathways in the osteoarthritis model differed from those in the control model. Several proteins differentially expressed at 4 weeks postoperatively may be involved in the pathogenesis of osteoarthritis and serve as potential biomarkers of early-stage osteoarthritis.