Roles of the aryl hydrocarbon receptor and its ligands in osteoclast differentiation and temporomandibular joint osteoarthritis

Background: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays an essential role in skeletal homeostasis. Increasing evidence indicates that AhR critically regulates osteoclast differentiation and activity, thereby influencing bone mass, bone resorption, and susceptibility to skeletal diseases. Although AhR has also been implicated in osteoblast-lineage cells, its regulatory roles in osteoclasts and immune cells are less well understood but are increasingly recognized as central to bone remodeling. In particular, AhR signaling modulates immune cell subsets relevant to bone metabolism and governs the differentiation of bone marrow-derived macrophages into osteoclasts.
Highlight: This review summarizes the recent findings regarding the regulation of osteoclast differentiation by AhR and its ligands under both physiological and pathological conditions. Special emphasis is placed on the interaction between AhR and the RANKL signaling axis in osteoclasts, as well as on how exogenous and endogenous ligands, including benzo[a]pyrene (B[a]P) and 6-formylindolo[3,2-b]carbazole (FICZ), modulate bone resorption and subchondral bone remodeling in temporomandibular joint osteoarthritis. Furthermore, the role of macrophages as osteoclast progenitors and immunomodulators has been highlighted, positioning AhR as a critical intermediary that links environmental exposure, inflammation, and skeletal metabolism.
Conclusion: In this review, we outlined the diverse functions of AhR signaling and its ligands in oral and temporomandibular joint osteoarthritis. AhR plays a central role in bone remodeling. The harmful exogenous ligand B[a]P generally promotes bone loss, whereas the endogenous ligand FICZ exerts protective actions. These insights highlight AhR as a key regulatory switch linking the skeletal and immune systems and as a promising therapeutic target for bone-destructive disorders.