Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis.
Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis.
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DOI：
10.3390/ijms23147995
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发表时间：
2022-07-20
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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核因子-κB (NF-κB) 转录因子家族由五种相关蛋白组成：RelA (p65)、c-Rel、RelB、p50/p105 (NF-κB1) 和 p52/p100 (NF-κB2)。这些蛋白质不仅对炎症和免疫反应很重要，而且对骨代谢也很重要。 NF-κB 的激活通过经典途径和替代途径发生。炎症细胞因子，如肿瘤坏死因子 (TNF)-α 和白细胞介素 (IL)-1β，激活前者，而参与淋巴结形成的细胞因子，如 NF-κB 配体受体激活剂 (RANKL) 和 CD40L，激活后者。 p50和p52双敲除小鼠由于完全缺乏破骨细胞而表现出严重的骨硬化症，破骨细胞是骨吸收的专门细胞。这一发现表明 NF-κB 的激活是破骨细胞分化所必需的。 NF-κB 信号通路受多种调节因子控制，包括由 IKBKG 基因编码的 NF-κB 必需调节因子 (NEMO)。近年来，IKBKG 基因的突变形式已被报道为骨硬化症、淋巴水肿、少汗性外胚层发育不良和免疫缺陷（OL-EDA-ID）的致病基因。此外，首次报道了新生儿骨量高的新生儿中编码 RelA 的 RELA 基因发生突变。骨石症的特点是骨量弥漫性增加，其范围从新生儿中观察到的致命形式到成年期出现的无症状形式。这篇综述描述了在石骨病患者中发现的 NF-κB 信号分子的基因突变。
The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-κB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-κB is required for osteoclast differentiation. The NF-κB signaling pathway is controlled by various regulators, including NF-κB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-κB signaling molecules that have been identified in patients with osteopetrosis.
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作者：
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影响因子：
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