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Objective. Females have reduced osteoarthritis (OA) in surgical models. The objective of the current study was to evaluate a sex-linked gut microbiome in the pathogenesis of OA. Methods. We induced OA via destabilization of the medial meniscus surgery in adult male and female C57BL6/J mice with and without opposite-sex microbiome transplantation. Eight weeks later, animals were euthanized, and OA severity, synovitis, and osteophyte scores were determined. Serum lipopolysaccharide was measured chromogenically, and serum cytokines were quantified via multiplex immunoassay. Cecal microbiome profiles were generated using 16S deep sequencing. Results. Males had worse OA histology (3.5x, P = 6 × 10−7 ), synovitis (2.4x, P = 5 × 10−4 ), and osteophyte scores (3.7x, P = 3 × 10−4 ) than females. Male-into-female transplantation worsened all outcomes (histology 1.8x, P = 0.02; synovitis 2.0x, P = 3 × 10−5 ; osteophyte 2.1x, P = 0.01) compared to females, whereas female-into-male transplantation improved all outcomes except for synovitis (histology 0.53x, P = 2 × 10−4 ; osteophyte 0.28x, P = 5 × 10−4 ) compared to males. In the gut microbiome analysis, 44 clades were different in at least one group comparison; 5 clades were correlated with the Osteoarthritis Research Society International score (Lactobacillus R = −0.40, Aldercreutzia R = −0.40, rc4_4 R = −0.55, Sutterella R = −0.37, and Clostridiales R = 0.36). In the cytokine analysis, 10 analytes were different in at least one group comparison; 3 were different in two groups (female and female-into-male transplants vs male comparisons, all reduced in female and female-into-male transplants), including interleukin-12 (0.66x, P = 0.02; 0.66x, P = 0.02, respectively), eotaxin (0.74x, P = 5 × 10−6 ; 0.57x, P = 0.03), and tumor necrosis factor α (0.49x, P = 0.03; 0.52x, P = 0.009). Conclusion. Sex-linked differences in the mouse gut microbiome are associated with OA outcomes, are reversible by opposite-sex microbiome transplantation, and are associated with serum cytokine changes. [ABSTRACT FROM AUTHOR]

Objective: The lack of accurate biomarkers to predict knee osteoarthritis (OA) progression is a key unmet need in OA clinical research. The objective of this study was to develop baseline peripheral blood epigenetic biomarker models to predict knee OA progression. Methods: Genome‐wide buffy coat DNA methylation patterns from 554 individuals from the Osteoarthritis Biomarkers Consortium (OABC) were determined using Illumina Infinium MethylationEPIC 850K arrays. Data were divided into model development and validation sets, and machine learning models were trained to classify future OA progression by knee pain, radiographic imaging, knee pain plus radiographic imaging, and any progression (pain, radiographic, or both). Parsimonious models using the top 13 CpG sites most frequently selected during development were tested on independent samples from participants in the Johnston County Osteoarthritis (JoCo OA) Project (n = 128) and a previously published Osteoarthritis Initiative (OAI) data set (n = 55). Results: Full models accurately classified future radiographic‐only progression (mean ± SEM accuracy 87 ± 0.8%, area under the curve [AUC] 0.94 ± 0.004), pain‐only progression (accuracy 89 ± 0.9%, AUC 0.97 ± 0.004), pain plus radiographic progression (accuracy 72 ± 0.7%, AUC 0.79 ± 0.006), and any progression (accuracy 78 ± 0.4%, AUC 0.86 ± 0.004). Pain‐only and radiographic‐only progressors were not distinguishable (mean ± SEM accuracy 58 ± 1%, AUC 0.62 ± 0.001). Parsimonious models showed similar performance and accurately classified future radiographic progressors in the OABC cohort and in both validation cohorts (mean ± SEM accuracy 80 ± 0.3%, AUC 0.88 ± 0.003 [using JoCo OA Project data], accuracy 80 ± 0.8%, AUC 0.89 ± 0.002 [using previous OAI data]). Conclusion: Our data suggest that pain and structural progression share similar early systemic immune epigenotypes. Further studies should focus on evaluating the pathophysiologic consequences of differential DNA methylation and peripheral blood cell epigenotypes in individuals with knee OA. [ABSTRACT FROM AUTHOR]