Xu Jiake, Wu Hua Fei, Ang Estabelle S M, Yip Kirk, Woloszyn Magdalene, Zheng Ming H, Tan Ren Xiang
Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Nedlands, Australia.
Cytokine Growth Factor Rev. 2009 Feb;20(1):7-17. doi: 10.1016/j.cytogfr.2008.11.007. Epub 2008 Nov 28.
Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-kappaB is a set of nuclear factors that bind to consensus DNA sequences called kappaB sites, and is essential for osteoclast formation and survival. NF-kappaB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-alpha and IL-1, which differentially regulate classical and/or alternative NF-kappaB pathways in osteoclastic cells. These pathways are also modulated by NF-kappaB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin-proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-kappaB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-kappaB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-kappaB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases.
破骨细胞负责骨吸收，并在溶骨性疾病的发病机制中起关键作用。核因子κB是一组与称为κB位点的共有DNA序列结合的核因子，对破骨细胞的形成和存活至关重要。核因子κB信号通路受到严格调控，以通过细胞因子如RANKL、肿瘤坏死因子-α和白细胞介素-1维持骨稳态，这些细胞因子在破骨细胞中差异调节经典和/或替代核因子κB通路。这些通路也受到核因子κB介质的调节，包括TRAF6、非典型蛋白激酶C、p62/SQSTM1和去泛素化酶CYLD，它们在RANK介导的破骨细胞生成过程中参与泛素-蛋白酶体系统。破骨细胞中核因子κB信号的异常激活与破骨细胞活性过度相关，并经常在溶骨性疾病中观察到，包括假体周围骨溶解、关节炎、佩吉特骨病和牙周炎。核因子κB调节剂如小白菊内酯和核因子κB必需调节蛋白结合域肽在小鼠模型中对炎症诱导的骨破坏具有治疗作用。阐明破骨细胞和其他细胞类型中核因子κB通路的结构和功能对于开发治疗骨疾病的新策略至关重要。
