Targeting Dkk1 Prevents Development Of Alcohol-Induced Osteonecrosis Of The Femoral Head In Rats

Osteonecrosis of the femoral head (ONFH) is a devastating bone disease characterized by avascular or aseptic necrosis of the femoral head, and alcohol consumption is reported one of the leading risks to this disease. Previous studies have linked Dickkopf-1 (DKK1) to the occurrence of ONFH, but the role of DKK1 in alcohol-induced ONFH (AONFH) has not been fully discussed. In this study, we found that the expression level of DKK1 was dramatically increased in serum and bone samples from AONFH patients, experimental AONFH rats, and cultured bone marrow mesenchymal stem cells (BMMSCs) with ethanol stimulation. Elevated DKK1 inhibited Wnt/beta-catenin signaling in vivo and in vitro, while knockdown of DKK1 enhanced the nuclear translocation of beta-catenin and promoted osteogenesis and inhibited adipogenesis in the BMMSC cell line C3H10T1/2. Local injection of DKK1 knockout lentivirus into the femoral head of rats alleviated the progression of AONFH, with activated Wnt/beta-catenin signaling, increased bone formation, reduced number of empty adipose lacunae and restored blood supply. In conclusion, our findings confirmed the important role of DKK1 and canonical Wnt/beta-catenin pathway in AONFH. We propose that DKK1 may be a prognostic marker of AONFH and targeting DKK1 to activate the canonical Wnt/beta-catenin pathway and restore osteogenic potential could be a promising therapeutic strategy to prevent AONFH.