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TNFR2 Agonism as a Sex-Specific Therapy for Novel Osteoarthritis-Induced Cardiac Dysfunction
Pranav Prasoon1, Kelly Tammen1, Rebekah Russo1
1Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Insights
Osteoarthritis causes sex-specific heart problems in mice, with females developing diastolic dysfunction and males systolic issues. Tumor necrosis factor 2 (TNFR2) agonism offers a promising therapeutic approach for these conditions.
Area of Science:
- Cardiovascular Biology
- Rheumatology
- Immunology
Background:
- Osteoarthritis (OA) is linked to increased systemic inflammation, chronic pain, and cardiovascular dysfunction.
- Epidemiological studies show OA triples the risk of cardiovascular disease (CVD), but the causal link is understudied.
- Preclinical models linking joint disease to cardiac dysfunction are lacking.
Purpose of the Study:
- To assess cardiac function longitudinally after inducing OA in mice using destabilization of the medial meniscus (DMM) surgery.
- To investigate the sexually dimorphic cardiac phenotypes in an OA mouse model.
- To evaluate the therapeutic potential of tumor necrosis factor 2 (TNFR2) agonism in OA-induced cardiovascular dysfunction.
Main Methods:
- Induction of osteoarthritis in mice via destabilization of the medial meniscus (DMM) surgery.
- Longitudinal assessment of cardiac function using echocardiography.
- Transcriptomic profiling and biochemical analyses to explore cellular responses.
- Administration of a tumor necrosis factor 2 (TNFR2) agonist for prophylactic and therapeutic evaluation.
Main Results:
- DMM surgery induced significant, sexually dimorphic alterations in cardiac function.
- Female DMM mice developed diastolic dysfunction (impaired relaxation), while male DMM mice exhibited progressive systolic dysfunction.
- Transcriptomic and biochemical analyses revealed divergent cellular responses: fibrosis and oxidative stress in females, autophagy and apoptosis in males.
- TNFR2 agonism was effective in preventing and treating diastolic dysfunction in females and delayed systolic dysfunction in males.
Conclusions:
- Osteoarthritis induces sex-specific cardiac phenotypes in a murine model, mirroring human patient patterns.
- Selective TNFR2 agonism demonstrates therapeutic potential for OA-induced cardiovascular dysfunction, with sex-specific efficacy.
- Findings support sex-dependent cardiac monitoring in OA patients and suggest TNFR2-targeted therapy as a sex-informed intervention.
Abstract:
Osteoarthritis (OA), a degenerative joint disease, is associated with increased systemic inflammation, chronic pain, and cardiovascular dysfunction. Epidemiological evidence establishes that OA increases the risk of cardiovascular disease (CVD) threefold, yet the causal role of OA's contributions remains underexamined. We assessed cardiac function longitudinally following destabilization of the medial meniscus (DMM) surgery to induce osteoarthritis in mice. DMM-mice exhibited significant, sexually dimorphic alterations in echocardiographic parameters. Female DMM mice developed impaired relaxation with altered E/A ratios, increased E/e' ratios, and prolonged intraventricular relaxation time with no change in ejection fraction, while male DMM mice showed progressive systolic dysfunction with decreasing ejection fraction, increased E/e' ratio, and prolonged intraventricular contraction time. Transcriptomic profiles and biochemical analyses demonstrated divergent cellular responses involving fibrosis and oxidative stress in female mice, whereas autophagic and apoptotic responses were observed in male mice. Using a tumor necrosis factor 2 (TNFR2) agonist shown to reduce systemic inflammation, we investigated its potential therapeutic role in the context of OA-induced cardiovascular dysfunction. TNFR2 agonism proved to be effective both prophylactically and therapeutically for female diastolic dysfunction. While prophylactic and therapeutic administration delayed male systolic dysfunction, the efficacy declined over time. Our findings demonstrate evidence of a novel sexually dimorphic model of OA-induced CVD that recapitulates the sexually dimorphic pattern of patient phenotypes and a promising new therapeutic approach to CVD.
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