Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; Department of Anatomy and Cell Biology, Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul, Korea.
J Cell Physiol. 2014 Dec;229(12):1963-71. doi: 10.1002/jcp.24646.
Beclin-1 plays a critical role in autophagy; however, it also contributes to other biological processes in a non-autophagic manner. Although studies have examined the non-autophagic role of autophagy proteins in the secretory function of osteoclasts (OC), the role of Beclin-1 is unclear. Here, we examined the role of Beclin-1 in OC differentiation, and found that mouse bone marrow macrophages (BMMs) showed increased expression of Beclin-1 upon RANKL stimulation in a p38- and NF-kappa B-dependent manner. During OC differentiation, Beclin-1 localized to the mitochondria, where it was involved in the production of mitochondrial intracellular reactive oxygen species. Knockdown of Beclin-1 in RANKL-primed BMMs led to a significant reduction in RANKL-dependent osteoclastogenesis, which was accompanied by reduced NFATc1 induction. Furthermore, knockdown of Beclin-1 inhibited RANKL-mediated activation of JNK and p38, both of which act downstream of reactive oxygen species, resulting in the suppression of NFATc1 induction. Finally, overexpression of constitutively active NFATc1 rescued the phenotype induced by Beclin-1 knockdown, indicating that Beclin-1 mediates RANKL-induced osteoclastogenesis by regulating NFATc1 expression. These findings show that Beclin-1 plays a non-autophagic role in RANKL-induced osteoclastogenesis by inducing the production of reactive oxygen species and NFATc1.
Beclin-1 在自噬中发挥着关键作用；然而，它也以非自噬的方式参与其他生物过程。尽管已有研究探讨了自噬蛋白在破骨细胞（OC）分泌功能中的非自噬作用，但 Beclin-1 的作用尚不清楚。在这里，我们研究了 Beclin-1 在 OC 分化中的作用，发现 RANKL 刺激以 p38 和 NF-κB 依赖的方式增加了小鼠骨髓巨噬细胞（BMM）中 Beclin-1 的表达。在 OC 分化过程中，Beclin-1 定位于线粒体，参与线粒体细胞内活性氧的产生。在 RANKL 诱导的 BMM 中敲低 Beclin-1 会导致 RANKL 依赖性破骨细胞生成显著减少，同时 NFATc1 的诱导减少。此外，Beclin-1 的敲低抑制了 RANKL 介导的 JNK 和 p38 的激活，这两者都作用于活性氧的下游，从而抑制 NFATc1 的诱导。最后，组成型激活的 NFATc1 的过表达挽救了由 Beclin-1 敲低引起的表型，表明 Beclin-1 通过调节 NFATc1 的表达介导 RANKL 诱导的破骨细胞生成。这些发现表明 Beclin-1 通过诱导活性氧和 NFATc1 的产生在 RANKL 诱导的破骨细胞生成中发挥非自噬作用。
