Expression of the aryl hydrocarbon receptor in Osterix-lineage cells regulates adult skeletal homeostasis in a compartment-specific manner

Kynurenine (KYN), a tryptophan metabolite that increases with age, impairs osteoblast function. The aryl hydrocarbon receptor (AhR) has been proposed to mediate KYN's actions in bone. To test whether deletion of AhR in osteoblasts is beneficial for bone, we established an adult-onset AhR conditional knockout (CKO) model using Osx-Cre and examined the effects of AhR CKO at 4.5 and 6 mo of age (representing ~6 and 12 wk of CKO). While BMSC-derived osteoblasts from WT mice demonstrated reduced matrix formation from KYN treatment, AhR CKO osteoblasts were unaffected by KYN. Kynurenine's harmful effects were most pronounced in the middle of an osteoblastic differentiation time course, and these effects could be rescued via the AhR antagonist BAY2416964. In vivo, AhR deletion in Osx-expressing cells promoted sex- and compartment-specific skeletal phenotypes. Trabecular bone was increased in the distal femur of male and female AhR CKO mice at both 4.5 and 6 mo of age, potentially driven by a net decrease in the ratio of trabecular osteoclasts to osteoblasts despite a reduction in mineral apposition rate at 6 mo of age. In contrast, cortical bone phenotypes induced by AhR deletion depended on age and sex. In males, cortical bone volume fraction (Ct.BV/TV) was elevated in AhR CKO mice vs WT littermates at 4.5 mo of age, but differences resolved by 6 mo of age. In contrast, cortical bone was reduced in female AhR CKO as compared to WT littermates at 6 mo of age. These results underscore the complexity of AhR signaling in skeletal biology that must be considered while exploring AhR as a therapeutic target for conditions like osteoporosis and musculoskeletal frailty. Future studies will be needed to test the effects of osteoblastic AhR deletion at advanced ages, when the endogenous AhR ligand KYN is elevated in the circulation and skeletal niche.