Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
Int J Mol Sci. 2021 Mar 12;22(6):2893. doi: 10.3390/ijms22062893.
Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in , which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.
脂肪酶 2 是一种磷酸二酯酶，在脂肪稳态中发挥关键作用。编码脂肪酶 2 的基因发生改变会导致自身炎症性骨病 Majeed 综合征。脂肪酶 2 限制了巨噬细胞中脂多糖 (LPS) 诱导的炎症反应。然而，其抗炎功能的确切分子机制知之甚少。在这项研究中，我们试图阐明脂肪酶 2 功能丧失与自身炎症性骨病之间的分子联系。使用脂肪酶 2 敲除的小鼠巨噬细胞系，我们表明脂肪酶 2 缺乏通过过度激活 NF-κB 信号通路增强了对 LPS 刺激的固有免疫反应，部分原因是 TAK1 信号上调。脂肪酶 2 耗竭还增强了 RANKL 介导的破骨细胞生成和破骨细胞吸收活性，伴随着 NFATc1 的去磷酸化和核内积累增加。这些结果表明，脂肪酶 2 通过精细调节巨噬细胞中的促炎反应和破骨细胞生成来抑制自身炎症性骨病的发展。因此，本研究为单基因自身炎症性骨病的分子发病机制提供了新的见解，并提出了一种潜在的治疗干预措施。
