Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.
Division of Orofacial Functions and Orthodontics, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.
PLoS One. 2022 Feb 23;17(2):e0262612. doi: 10.1371/journal.pone.0262612. eCollection 2022.
Orthodontic treatment requires the regulation of bone remodeling in both compression and tension sides. Transforming growth factor-β1 (TGF-β1) is an important coupling factor for bone remodeling. However, the mechanism underlying the TGF-β1-mediated regulation of the osteoclast-supporting activity of osteoblasts and stromal cells remain unclear. The current study investigated the effect of TGF-β1 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in stromal cells induced by 1α,25(OH)2D3 (D3) and dexamethasone (Dex). TGF-β1 downregulated the expression of RANKL induced by D3 and Dex in mouse bone marrow stromal lineage, ST2 cells. Co-culture system revealed that TGF-β1 suppressed osteoclast differentiation from bone marrow cell induced by D3 and Dex-activated ST2 cells. The inhibitory effect of TGF-β1 on RANKL expression was recovered by inhibiting the interaction between TGF-β1 and the TGF-β type I/activin receptor or by downregulating of smad2/3 expression. Interestingly, TGF-β1 degraded the retinoid X receptor (RXR)-α protein which forms a complex with vitamin D receptor (VDR) and regulates transcriptional activity of RANKL without affecting nuclear translocation of VDR and phosphorylation of signal transducer and activator of transcription3 (STAT3). The degradation of RXR-α protein by TGF-β1 was recovered by a ubiquitin-proteasome inhibitor. We also observed that poly-ubiquitination of RXR-α protein was induced by TGF-β1 treatment. These results indicated that TGF-β1 downregulates RANKL expression and the osteoclast-supporting activity of osteoblasts/stromal cells induced by D3 and Dex through the degradation of the RXR-α protein mediated by ubiquitin-proteasome system.
正畸治疗需要调节压缩侧和拉伸侧的骨重塑。转化生长因子-β1（TGF-β1）是骨重塑的重要偶联因子。然而，TGF-β1 介导的调节成骨细胞和基质细胞的破骨细胞支持活性的机制尚不清楚。本研究探讨了 TGF-β1 对 1α，25（OH）2D3（D3）和地塞米松（Dex）诱导的基质细胞中核因子κB 受体激活剂配体（RANKL）表达的影响。TGF-β1 下调了 D3 和 Dex 诱导的小鼠骨髓基质谱系 ST2 细胞中 RANKL 的表达。共培养系统显示，TGF-β1 抑制了 D3 和 Dex 激活的 ST2 细胞诱导的骨髓细胞来源的破骨细胞分化。TGF-β1 对 RANKL 表达的抑制作用可通过抑制 TGF-β1 与 TGF-β Ⅰ/激活素受体的相互作用或下调 smad2/3 表达来恢复。有趣的是，TGF-β1 降解了视黄醇 X 受体（RXR）-α 蛋白，该蛋白与维生素 D 受体（VDR）形成复合物，调节 RANKL 的转录活性，而不影响 VDR 的核转位和信号转导和转录激活因子 3（STAT3）的磷酸化。TGF-β1 降解 RXR-α 蛋白可被泛素-蛋白酶体抑制剂所恢复。我们还观察到 TGF-β1 处理诱导 RXR-α 蛋白多泛素化。这些结果表明，TGF-β1 通过泛素-蛋白酶体系统介导的 RXR-α 蛋白降解，下调 D3 和 Dex 诱导的 RANKL 表达和成骨细胞/基质细胞的破骨细胞支持活性。
