AhR signaling in joint homeostasis and disease.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that integrates environmental, microbial, and metabolic signals to regulate gene expression across diverse tissues. Recent studies highlight AhR's role in skeletal homeostasis and joint biology, particularly through its interactions with microbiome-derived tryptophan metabolites and the Wnt/β-catenin signaling pathway. This review synthesizes current knowledge on AhR signaling mechanisms, including canonical and non-canonical pathways, and explores the impact of exogenous toxicants and microbiome-derived compounds and endogenous host metabolites that activate AhR. We discuss emerging evidence linking AhR activity to cartilage development, inflammation, and osteoarthritis progression, and highlight the utility of gnotobiotic mouse models in dissecting microbiome-AhR interactions. Finally, we examine the therapeutic potential of AhR modulation in joint disease, emphasizing its relevance as a pharmaceutical target for osteoarthritis and age-related musculoskeletal decline.