Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
FASEB J. 2018 Jun;32(6):3215-3228. doi: 10.1096/fj.201600825RRR. Epub 2018 Jan 22.
REV-ERBs (REV-ERBα and REV-ERBβ) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV-ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBα level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs). REV-ERBα knockdown by small interfering RNA in BMMs resulted in the enhanced formation of osteoclasts, whereas REV-ERBβ knockdown showed no effect on osteoclast differentiation. Moreover, the REV-ERB agonist SR9009 inhibited osteoclast differentiation and bone resorption. Intraperitoneal SR9009 administration prevented ovariectomy-induced bone loss; this effect was accompanied by decreased serum RANKL and C-terminal telopeptide of type I collagen levels and increased osteoprotegerin levels. Further investigation revealed that NF-κB and MAPK activation and nuclear factor of activated T cells, cytoplasmic 1, and c-fos expression were suppressed by SR9009. The level of reactive oxygen species was also decreased by SR9009, with NADPH oxidase subunits also being down-regulated. In addition, an expression microarray showed that FABP4, an intracellular lipid-binding protein, was up-regulated by REV-ERB agonism. BMS309403, an inhibitor of FABP4, partially prevented the suppression of osteoclastogenesis by SR9009 through stabilizing phosphorylation of p65. To summarize, our results proved that the REV-ERB agonism inhibited osteoclastogenesis partially via FABP4 up-regulation.-Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.
REV-ERBs（REV-ERBα 和 REV-ERBβ）是转录抑制剂和昼夜节律调节剂。先前的研究表明，REV-ERBs 可抑制 MMP9 和 CX3CR1 等靶基因在巨噬细胞中的表达。因为 MMP9 和 CX3CR1 据报道参与核因子-κB 配体（RANKL）诱导的破骨细胞生成，我们推断 REV-ERBs 可能在破骨细胞生成中发挥作用。在本研究中，我们发现在 RANKL 诱导的原代骨髓来源巨噬细胞（BMM）破骨细胞分化过程中，REV-ERBα 水平显著降低。在 BMM 中用小干扰 RNA 敲低 REV-ERBα 导致破骨细胞形成增强，而敲低 REV-ERBβ 对破骨细胞分化没有影响。此外，REV-ERB 激动剂 SR9009 抑制破骨细胞分化和骨吸收。腹腔内给予 SR9009 可防止卵巢切除引起的骨丢失；这种作用伴随着血清 RANKL 和 I 型胶原 C 末端肽水平的降低以及骨保护素水平的升高。进一步的研究表明，SR9009 抑制 NF-κB 和 MAPK 激活以及活化 T 细胞核因子细胞质 1 和 c-fos 的表达。SR9009 还降低了活性氧的水平，并下调 NADPH 氧化酶亚基。此外，表达微阵列显示，细胞内脂质结合蛋白 FABP4 被 REV-ERB 激动剂上调。FABP4 抑制剂 BMS309403 通过稳定 p65 的磷酸化部分阻止了 SR9009 对破骨细胞生成的抑制。综上所述，我们的结果证明，REV-ERB 激动剂通过上调 FABP4 部分抑制破骨细胞生成。-宋晨，谭平，张泽，吴伟，董阳，赵琳，刘欢，关宏，李芳。REV-ERB 激动剂通过上调 FABP4 部分抑制破骨细胞生成并防止卵巢切除引起的骨丢失。
