Chen Jinzhong, Yang Chengliang, Yang Ye, Liang Qingyang, Xie Kegong, Liu Jia, Tang Yujin
Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities Baise 533000, Guangxi, China.
Youjiang Medical University for Nationalities Baise 533000, Guangxi, China.
Am J Transl Res. 2021 Apr 15;13(4):2320-2330. eCollection 2021.
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/β-catenin signaling and , while knockdown of DKK1 enhanced the nuclear translocation of β-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/β-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/β-catenin pathway in AONFH. We propose that DKK1 may be a prognostic marker of AONFH and targeting DKK1 to activate the canonical Wnt/β-catenin pathway and restore osteogenic potential could be a promising therapeutic strategy to prevent AONFH.
股骨头坏死（ONFH）是一种破坏性骨疾病，其特征为股骨头的缺血性或无菌性坏死，据报道，饮酒是该疾病的主要风险之一。以往研究已将Dickkopf-1（DKK1）与ONFH的发生联系起来，但DKK1在酒精性股骨头坏死（AONFH）中的作用尚未得到充分探讨。在本研究中，我们发现，在AONFH患者、实验性AONFH大鼠以及经乙醇刺激的培养骨髓间充质干细胞（BMMSC）的血清和骨样本中，DKK1的表达水平显著升高。升高的DKK1抑制Wnt/β-连环蛋白信号传导，而敲低DKK1则增强了β-连环蛋白的核转位，并促进了BMMSC细胞系C3H10T1/2中的成骨作用并抑制了脂肪生成。向大鼠股骨头局部注射DKK1基因敲除慢病毒可缓解AONFH的进展，激活Wnt/β-连环蛋白信号传导，增加骨形成，减少空脂肪腔数量并恢复血液供应。总之，我们的研究结果证实了DKK1和经典Wnt/β-连环蛋白通路在AONFH中的重要作用。我们提出，DKK1可能是AONFH的一个预后标志物，靶向DKK1以激活经典Wnt/β-连环蛋白通路并恢复成骨潜能可能是一种有前景的预防AONFH的治疗策略。
