Aryl hydrocarbon receptor (AhR)-mediated signaling as a critical regulator of skeletal cell biology

The aryl hydrocarbon receptor (AhR) has been implicated in regulating skeletal progenitor cells and the activity of bone-forming osteoblasts and bone-resorbing osteoclasts, thereby impacting bone mass and the risk of skeletal fractures. The AhR also plays an important role in the immune system within the skeletal niche and in the differentiation of mesenchymal stem cells into other cell lineages including chondrocytes and adipocytes. This transcription factor responds to environmental pollutants which can act as AhR ligands, initiating or interfering with various signaling cascades to mediate downstream effects, and also responds to endogenous ligands including tryptophan metabolites. This review comprehensively describes the reported roles of the AhR in skeletal cell biology, focusing on mesenchymal stem cells, osteoblasts, and osteoclasts, and discusses how AhR exhibits sexually dimorphic effects in bone. The molecular mechanisms mediating AhR's downstream effects are highlighted to emphasize the potential importance of targeting this signaling cascade in skeletal disorders.