The cannabinoid receptor 2 is an in vivo receptor of bisphenol A during bone formation

Osteoporosis is a bone disorder characterized by decreased bone mass and increased risk of fractures afffecting over 200 million people worldwide. Currently the causes of osteoporosis are not well understood preventing an effective treatment for this disease. However, exposure to a common class of xenoestrogens known as bisphenols has been linked to this disorder. Our findings demonstrate that exposure to Bisphenol A (BPA) and its proposed replacements, bisphenol S (BPS) and tetrabromobisphenol A (TBBPA), reduces osteoblast number and calcification at environmentally relevant doses during zebrafish development. Transcriptomic analysis of osteoblast cells sorted after BPA exposure, revealed that the endocannabinoid pathway is one of the primary pathways disrupted. Bone growth is connected to the endocannabinoid system through cannabinoid receptor 1 (CB1) and 2 (CB2). Pharmacological activation of this pathway, combined with bisphenol exposure, has additive effects that further reduces osteoblast numbers and bone calcification. Exposure of CB1 or CB2 loss-of-function zebrafish mutants to bisphenols revealed that only the loss of CB2 prevents bisphenol induced bone defects. Furthermore, molecular docking analysis predicted that BPA, BPS, and TBBPA bind to the CB2 receptor with high affinity. Collectively, our data identifies CB2 as a novel receptor for bisphenol-mediated induction of bone defects in vivo.