Effect of S1P/S1PR on bone metabolism in bisphosphonate-related osteonecrosis of the jaws

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a major adverse effect of bisphosphonates, yet its underlying pathogenesis remains poorly understood. Bone metabolism and remodeling relies on the interaction between osteoblasts (OBs) and osteoclasts (OCs). Sphingosine 1-phosphate (S1P), a bioactive sphingolipid metabolite, is an important mediator of OC-OB communication. In this study, we aimed to investigate the role of the S1P/S1P receptor (S1PR) axis in the development of BRONJ. A co-culture system was used to examine the interaction between OCs and OBs. Western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression of related proteins and messenger ribonucleic acids (mRNAs). Finally, an in vivo BRONJ mouse model was used to validate the role of S1P/S1PR axis in disease progression. In our study, we showed that zoledronate (ZOL) promoted S1P secretion from OCs and enhanced the migration of osteoclast precursor cells (OCPs) through S1PR signaling. In addition, OCs promoted the excessive osteogenic differentiation and migration of OBs via S1P/S1PR axis. Importantly, pharmacological inhibition of S1PR facilitated the recovery of BRONJ-like lesions in vivo. In conclusion, these findings indicate that the S1P/S1PR axis plays an important role in the pathogenesis of BRONJ and may represent a potential therapeutic target for its treatment.