KLF2 (kruppel like factor 2 [lung]) regulates osteoclastogenesis by modulating autophagy
KLF2 (kruppel like factor 2 [lung]) regulates osteoclastogenesis by modulating autophagy
复制标题
DOI：
10.1080/15548627.2019.1596491
复制
发表时间：
2019-04-18
期刊：
影响因子：
13.3
通讯作者：
Das, Hiranmoy
中科院分区：
文献类型：
--
作者：
Laha, Dipranjan;Deb, Moonmoon;Das, Hiranmoy
巨自噬/自噬参与骨髓细胞修复、破坏和破骨细胞分化;相反，KLF 2（kruppel样因子2 [肺]）调节骨髓细胞活化和分化。为了研究KLF 2在自噬中的特定作用，在存在或不存在自噬抑制剂3-甲基腺嘌呤（3-MA）、KLF 2诱导剂香叶基香叶基转移酶抑制剂（GGTI 298）和腺病毒过表达KLF 2的情况下，在单核细胞中诱导骨细胞分化。我们发现，自噬细胞和多核破骨细胞的数量显着减少的存在下，3-MA，GGTI 298，和KLF 2过表达的细胞，表明在这些过程中的KLF 2参与。此外，自噬相关的蛋白分子显着减少后，诱导KLF 2在骨细胞分化的过程中。此外，在小鼠中诱导关节炎降低单核细胞中Klf 2的水平，并增强骨细胞分化期间的自噬。机制上，敲低KLF 2增加Beclin 1（BECN 1）表达水平，相反，KLF 2过表达降低单核细胞中BECN 1的水平。此外，3-MA和GGTI 298均减少骨髓细胞增殖，同时上调衰老相关分子（CDKN 1A/p21和CDKN 1B/p27（kip 1））。我们进一步证实了通过调节Klf 2对Becn 1进行表观遗传调控; Klf 2的敲低增加了Becn 1启动子区域中组蛋白激活标记H3 K9和H4 K8乙酰化的水平; Klf 2的过表达降低了H4 K8和H3 K9乙酰化的水平。此外，成骨细胞分化也增加了Becn 1启动子区H3 K9和H4 K8乙酰化水平。这些发现首次揭示了Klf 2在破骨细胞生成过程中对Becn 1介导的自噬过程具有重要调控作用。
Macroautophagy/autophagy is involved in myeloid cellular repair, destruction, and osteoclast differentiation; conversely, KLF2 (kruppel-like factor 2 [lung]) regulates myeloid cell activation and differentiation. To investigate the specific role of KLF2 in autophagy, osteoclastic differentiation was induced in monocytes in presence or absence of the autophagy inhibitor 3-methyladenine (3-MA), KLF2 inducer geranylgeranyl transferase inhibitor (GGTI298), and adenoviral overexpression of KLF2. We found that the number of autophagic cells and multinucleated osteoclasts were significantly decreased in presence of 3-MA, GGTI298, and KLF2 overexpressed cells indicating involvement of KLF2 in these processes. In addition, autophagy-related protein molecules were significantly decreased after induction of KLF2 during the course of osteoclastic differentiation. Furthermore, induction of arthritis in mice reduced the level of Klf2 in monocytes, and enhanced autophagy during osteoclastic differentiation. Mechanistically, knocking down of KLF2 increased the level of Beclin1 (BECN1) expression, and conversely, KLF2 over-expression reduced the level of BECN1 in monocytes. Moreover, 3-MA and GGTI298 both reduced myeloid cell proliferation concomitantly upregulating senescence-related molecules (CDKN1A/p21 and CDKN1B/p27(kip1)). We further confirmed epigenetic regulation of Becn1 by modulating Klf2; knocking down of Klf2 increased the levels of histone activation marks H3K9 and H4K8 acetylation in the promoter region of Becn1; and overexpression of Klf2 decreased the levels of H4K8 and H3K9 acetylation. In addition, osteoclastic differentiation also increased levels of H3K9 and H4K8 acetylation in the promoter region of Becn1. Together these findings for the first time revealed that Klf2 critically regulates Becn1-mediated autophagy process during osteoclastogenesis.