SMU-KI United Medical Inflammatory Center, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
SMU-KI United Medical Inflammatory Center, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Pharmacol Res. 2021 Mar;165:105458. doi: 10.1016/j.phrs.2021.105458. Epub 2021 Jan 27.
Bone resorption by osteoclasts is an energy consuming activity, which depends on mitochondrial ATP. ATP5B, a mitochondrial ATP synthase beta subunit, is a catalytic core involved in producing ATP. Here, we investigated the contribution of ATP5B in osteoclast differentiation and joint destruction. ATP5B (LV-ATP5B) targeting or non-targeting (LV-NC) siRNA containing lentivirus particles were transduced into bone marrow macrophage derived osteoclasts or locally administered to arthritic mouse joints. Inhibition of ATP5B reduced the expression of osteoclast related genes and proteins, suppressed bone resorption by significantly impairing F-actin formation and decreased the levels of adhesion-associated proteins. In addition, ATP5B deficiency caused osteoclast mitochondrial dysfunction and, impaired the secretion of vacuole protons and MMP9. Importantly, inhibition of ATP5B expression, protected arthritis mice from joint destructions although serum levels of inflammatory mediators (TNF-α, IL-1β) and IgG2α antibodies were unaffected. These results demonstrate an essential function of ATP5B in osteoclast differentiation and bone resorption, and suggest it as a potential therapeutic target for protecting bones in RA.
破骨细胞的骨吸收是一种耗能活动，依赖于线粒体 ATP。ATP5B，一种线粒体 ATP 合酶β亚基，是参与产生 ATP 的催化核心。在这里，我们研究了 ATP5B 在破骨细胞分化和关节破坏中的作用。靶向 ATP5B（LV-ATP5B）或非靶向（LV-NC）siRNA 含慢病毒颗粒被转导到骨髓巨噬细胞来源的破骨细胞中，或局部施用于关节炎小鼠关节。ATP5B 的抑制降低了破骨细胞相关基因和蛋白的表达，通过显著损害 F-肌动蛋白的形成来抑制骨吸收，并降低粘附相关蛋白的水平。此外，ATP5B 缺乏导致破骨细胞线粒体功能障碍，并损害空泡质子和 MMP9 的分泌。重要的是，抑制 ATP5B 的表达，尽管血清中炎症介质（TNF-α、IL-1β）和 IgG2α 抗体的水平不受影响，但能保护关节炎小鼠免受关节破坏。这些结果表明 ATP5B 在破骨细胞分化和骨吸收中具有重要功能，并提示它作为保护 RA 中骨骼的潜在治疗靶点。
