<scp>Sex‐Linked</scp> Discrepancies in <scp>C57BL6</scp>/J Mouse Osteoarthritis are Associated With the Gut Microbiome and are Transferrable by Microbiome Transplantation

Schlupp, Leoni; Prinz, Emmaline; Dyson, Gabriella; Barrett, Montana; Izda, Vladislav; Dunn, Christopher M.; Jeffries, Matlock A.

doi:10.1002/art.42687

Cited by 2 publications

References 23 publications

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Transcutaneous Vagus Nerve Stimulation Reduces Pain and OA Progression in Mouse Models of Post-Traumatic Osteoarthritis

Yadav,

Morris,

Conner

et al. 2024

Preprint

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Currently, there are no disease-modifying osteoarthritis (OA) drugs (DMOAD) to prevent OA progression and there are limitations on pain relieving therapeutics. Vagus nerve stimulation (VNS) delivered by an implantable device is FDA-approved for refractory epilepsy and severe depression. Here, we investigated the efficacy of transcutaneous VNS (tVNS) for preventing OA progression and providing pain relief in two mouse models of post-traumatic OA (PTOA): the surgical destabilized medial meniscus (DMM) and the non-surgical forced tibial compression anterior cruciate ligament rupture (ACLR). Here, we show that 2 weeks of tVNS significantly reduced histological OA scores in male and female mice after ACLR compared to sham stimulation. In female, but not male, mice, tVNS reduced hyperalgesia and mechanical allodynia. In the slower DMM model, 8 weeks of tVNS improved weight bearing in male and female mice, but only female mice had improved hyperalgesia. Male mice had lower OA histological scores. Serum proinflammatory cytokines were significantly reduced by tVNS in both models but differed by gender and model. Overall, these results provide strong pre-clinical evidence that tVNS reduces OA progression, improves pain, and suppresses pro-inflammatory cytokines, making it a promising DMOAD.

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Transcutaneous Vagus Nerve Stimulation Reduces Pain and OA Progression in Mouse Models of Post-Traumatic Osteoarthritis

Yadav,

Morris,

Conner

et al. 2024

Preprint

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Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice

Griffin,

Lopes,

Cortassa

et al. 2024

Biol Sex Differ

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Background Women have a higher risk of developing osteoarthritis (OA) than men, including with obesity. To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA. Methods Male and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age (n = 12 per diet and sex). We performed broad metabolic phenotyping, 16 S gut microbiome analysis, targeted gene expression analysis of synovium-infrapatellar fat tissue, targeted gene expression and proteomic analysis of articular cartilage, chondrocyte metabolic profiling, and OA histopathology. Two-way ANOVA statistics were utilized to determine the contribution of sex and diet and their interaction on outcomes. Results Mice fed HFD weighed 1.76-fold (p < 0.0001) and 1.60-fold (p < 0.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 ± 2.2%; female: 44.1 ± 3.8%). HFD caused greater cartilage pathology (p < 0.024) and synovial hyperplasia (p < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (p = 0.048), and only male mice developed osteophytes with HFD (p = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (p < 0.0001), fatty liver (p < 0.0001), and elevated serum amylase (p < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (p = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of Bifidobacterium only in male mice. In knee synovium and infrapatellar fat tissue, HFD upregulated the expression of pro-inflammatory and pro-fibrotic genes predominantly in female mice. In cartilage, lipid metabolism proteins were more abundant with HFD in male mice, whereas proteins involved in glycolysis/gluconeogenesis and biosynthesis of amino acids were greater in cartilage of female mice. Sex-dependent metabolic differences were observed in cartilage from young, healthy mice prior to pubertal maturation, but not in primary juvenile chondrocytes studied in vitro. Conclusions HFD induced numerous sex differences in metabolic and inflammatory outcomes, especially in joint tissues, suggesting that sex-specific cellular processes are involved during development of early-stage OA with obesity.

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Sex‐Linked Discrepancies in C57BL6/J Mouse Osteoarthritis are Associated With the Gut Microbiome and are Transferrable by Microbiome Transplantation

Cited by 2 publications

References 23 publications

Transcutaneous Vagus Nerve Stimulation Reduces Pain and OA Progression in Mouse Models of Post-Traumatic Osteoarthritis

Transcutaneous Vagus Nerve Stimulation Reduces Pain and OA Progression in Mouse Models of Post-Traumatic Osteoarthritis

Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice

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