Osteoarthritis treatment via the GLP-1-mediated gut-joint axis targets intestinal FXR signaling.
Summary
Across human cohorts and mouse models, the authors identify a GLP-1–mediated gut–joint axis in osteoarthritis. Reduced GUDCA and FXR signaling modulate intestinal GLP-1, and pharmacologic manipulation of the GLP-1 receptor respectively attenuates or exacerbates osteoarthritic pathology.
Key Findings
- Two independent human cohorts showed altered microbial bile acid metabolism with reduced GUDCA in osteoarthritis.
- Suppressing intestinal FXR alleviated osteoarthritis in mice via intestine-secreted GLP-1.
- GLP-1 receptor blockade attenuated protective effects, whereas receptor activation mitigated osteoarthritic changes.
Clinical Implications
Suggests potential repurposing of GLP-1 receptor agonists and the development of intestinal FXR-modulating strategies for osteoarthritis; however, clinical trials are needed to confirm human efficacy and safety.
Why It Matters
It uncovers a mechanistic axis linking intestinal FXR signaling and GLP-1 to osteoarthritis, highlighting druggable pathways with immediate translational relevance given available GLP-1 receptor agonists.
Limitations
- Causality in humans is not established; clinical translation requires intervention trials
- Cohort sample sizes and detailed cohort characteristics are not specified in the abstract
Future Directions
Conduct randomized clinical trials of GLP-1 receptor agonists or FXR modulators in osteoarthritis, and delineate microbiome-bile acid contributors and biomarkers for patient stratification.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- II - Prospective/observational human cohorts complemented by mechanistic animal experiments supporting biological plausibility.
- Study Design
- OTHER