Department of Orthopedic Surgery, Department of Cell Biology & Physiology, Washington University School of Medicine, 660S. Euclid Avenue, Saint Louis, MO 63110, USA.
Osteoporos Int. 2013 Sep;24(9):2377-86. doi: 10.1007/s00198-013-2313-x. Epub 2013 Mar 7.
The transcription factor NF-κB is a family of proteins involved in signaling pathways essential for normal cellular functions and development. Deletion of various components of this pathway resulted with abnormal skeletal development. Research in the last decade has established that NF-κB signaling mediates RANK ligand-induced osteoclastogenesis. Consistently, it was shown that inhibition of NF-κB was an effective approach to inhibit osteoclast formation and bone resorptive activity. Identification of the molecular machinery underlying NF-κB activation permitted osteoclast-specific deletion of the major components of this pathway. As a result, it was clear that deletion of members of the proximal IKK kinase complex and the distal NF-κB subunits and downstream regulators affected skeletal development. These studies provided several targets of therapeutic intervention in osteolytic diseases. NF-κB activity has been also described as the centerpiece of inflammatory responses and is considered a potent mediator of inflammatory osteolysis. Indeed, inflammatory insults exacerbate physiologic RANKL-induced NF-κB signals leading to exaggerated responses and to inflammatory osteolysis. These superimposed NF-κB activities appear to underlie several bone pathologies. This review will describe the individual roles of NF-κB molecules in bone resorption and inflammatory osteolysis.
转录因子 NF-κB 是一组参与信号通路的蛋白质，这些信号通路对于正常细胞功能和发育至关重要。该通路的各种成分的缺失会导致骨骼发育异常。过去十年的研究已经确立，NF-κB 信号介导 RANKL 诱导的破骨细胞生成。一致地，抑制 NF-κB 是抑制破骨细胞形成和骨吸收活性的有效方法。对 NF-κB 激活的分子机制的鉴定允许对该途径的主要成分进行破骨细胞特异性缺失。结果表明，缺失近端 IKK 激酶复合物和远端 NF-κB 亚基以及下游调节剂会影响骨骼发育。这些研究为溶骨性疾病的治疗干预提供了多个靶点。NF-κB 活性也被描述为炎症反应的核心，被认为是炎症性骨溶解的有力介质。事实上，炎症刺激会加剧生理性 RANKL 诱导的 NF-κB 信号，导致过度反应和炎症性骨溶解。这些叠加的 NF-κB 活性似乎是几种骨病理学的基础。这篇综述将描述 NF-κB 分子在骨吸收和炎症性骨溶解中的作用。
