활성산소종이 파골세포 분화에 미치는 영향

Abstract

이 연구는 파골세포의 분화에 필수적인 수용체인 RANK의 신호전달경로에 활성화산소종이 중요한 역할을 한다는 것을 규명한 것으로, RANK 수용체의 리간드인 RANKL 처리에 의해 파골세포 내의 활성화산소종이 증가함을 확인하였다. 증가된 활성화산소종은 파골세포의 생존에 관여하는 신호전달물질인 Akt와 ERK, 그리고 NF-κB의 활성화를 촉진시켰으며, 항산화제에 의해 활성화가 억제됨을 확인하였다. 또한, 항산화제 처리에 의해 액틴고리 형성과 뼈흡수능이 억제됨을 관찰하였다. 이 결과는 활성화산소종과 관련된 신호전달경로의 억제제는 골흡수와 관련된 질환인 골다공증 치료제 개발의 중요한 후보물질로 사용될 수 있는 기초자료를 제공할 수 있을 것으로 사료된다.|RANKL, a member of tumor necrosis factor (TNF) superfamily, regulates the differentiation, activation, and survival of osteoclasts through binding with its cognate receptor, RANK. RANK can interact with several TNF receptor-associated factors (TRAFs) and activates signaling molecules including Akt, NF-κB, and MAPKs. However, the exact molecular mechanism of RANK signaling has not been fully elucidated. In the present work, the author demonstrated that reactive oxygen species (ROS) act as a signaling mediator of RANK in osteoclasts. Stimulation with RANKL induced ROS generation in osteoclasts. Two antioxidants, N-acetyl-L-cysteine and glutathione, prevented RANKL-induced Akt, NF-κB, and ERK activation in osteoclasts. TNF-α also increased ROS production in osteoclasts. However, antioxidants did not prevent TNF-α-induced Akt and NF-κB activation, while slightly affecting ERK activation. These results indicate that RANK initiates signaling through Akt and NF-κB pathways in a way that is different from TNFR. Pretreatment with antioxidants also significantly reduced RANKL-induced actin-ring formation, required for bone resorbing activity, and osteoclast survival. Taken together, these results suggest that ROS plays a critical role in RANK signaling and osteoclast function.