Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea; Department of Pathology, Ulsan University Hospital, Ulsan 682-714, Republic of Korea.
Biochem Pharmacol. 2018 May;151:9-17. doi: 10.1016/j.bcp.2018.02.019. Epub 2018 Feb 16.
4-Phenylbutyric acid (4-PBA) has been used clinically to treat urea cycle disorders and is known to be an inhibitor of endoplasmic reticulum (ER) stress. We hypothesized that 4-PBA attenuates inflammatory bone loss by inducing autophagy, a process that is frequently accompanied by ER stress. Micro computerized tomography analysis showed that 4-PBA attenuated LPS-induced bone loss in mice. The increased area of TRAP-positive osteoclasts (OCs) and serum level of collagen type I fragments in lipopolysaccharide (LPS)-treated mice were also decreased when 4-PBA was administered, suggesting a protective role of 4-PBA in OCs. In vitro, 4-PBA significantly reduced OC area without affecting the number of OCs induced by LPS and decreased bone resorption upon LPS stimulation. LPS-induced autophagy was attenuated by 4-PBA in OCs, as demonstrated by reduced LC3II accumulation, increased p62 level, and reduction in AVO-containing cells. Silencing of autophagy-related protein 7 attenuated the effects of 4-PBA on OC size and fusion. Moreover, 4-PBA reduced nuclear factor-κB (NF-κB) DNA binding upon LPS stimulation of OCs. Inhibition of NF-κB activation diminished the inhibitory effect of 4-PBA on LPS-stimulated changes in LC3II level, OC area, and OC fusion, implying that the effects of 4-PBA on OCs are due at least in part to inhibition of NF-κB. These data demonstrate that 4-PBA attenuates LPS-induced bone loss by reducing autophagy in OCs. Our data highlight the therapeutic potential of 4-PBA for ameliorating inflammatory bone loss.
4- 苯基丁酸（4-PBA）已被临床用于治疗尿素循环障碍，并且已知其是内质网（ER）应激的抑制剂。我们假设 4-PBA 通过诱导自噬来减轻炎症性骨丢失，自噬是一种经常伴随 ER 应激的过程。微计算机断层扫描分析表明，4-PBA 可减轻 LPS 诱导的小鼠骨丢失。当给予 4-PBA 时，还降低了 LPS 处理的小鼠中 TRAP 阳性破骨细胞（OC）的增加面积和胶原 I 片段的血清水平，这表明 4-PBA 在 OC 中具有保护作用。在体外，4-PBA 可显著减少 OC 面积，而不影响 LPS 诱导的 OC 数量，并减少 LPS 刺激时的骨吸收。4-PBA 减弱了 LPS 诱导的 OC 中的自噬，表现为 LC3II 积累减少，p62 水平增加，并且含有 AVO 的细胞减少。自噬相关蛋白 7 的沉默减弱了 4-PBA 对 OC 大小和融合的影响。此外，4-PBA 降低了 LPS 刺激 OC 时核因子-κB（NF-κB）DNA 结合。抑制 NF-κB 激活减弱了 4-PBA 对 LPS 刺激的 LC3II 水平、OC 面积和 OC 融合变化的抑制作用，表明 4-PBA 对 OC 的作用至少部分归因于 NF-κB 的抑制。这些数据表明，4-PBA 通过减少 OC 中的自噬来减轻 LPS 诱导的骨丢失。我们的数据突出了 4-PBA 用于改善炎症性骨丢失的治疗潜力。
