Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Department of Orthopedics & Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.
PLoS One. 2018 Jun 26;13(6):e0198326. doi: 10.1371/journal.pone.0198326. eCollection 2018.
Treatment for musculoskeletal fibromatosis remains challenging. Surgical excision for fibromatosis is the standard therapy but recurrence remains high. Corticosteroids, an anti-fibrogenic compound, have been used to treat early stage palmar fibromatosis, but the mechanism is unknown. We investigated the inhibitory mechanism effect of corticosteroids in the murine model of fibromatosis nodule as well as in cultured FSCs. Quantitative reverse transcription/polymerase chain reaction (PCR) analysis and immunofluorescence (IF) staining for markers of myofibroblasts (α-smooth muscle actin and type III collagen) were used to examine the effect of dexamethasone on myofibroblasic differentiation of FSCs both in vitro and in vivo. Transforming growth factor-β1 (TGF-β1) signaling and its downstream targets were examined using western blot analysis. TGF-β1 expression in FSCs before and after dexamethasone treatment was compared. In addition, inhibition of TGF-β1 expression was examined using RNA interference (RNAi) on FSCs, both in vitro and in vivo. Treating FSCs with dexamethasone inhibited FSCs' myofibroblastic differentiation in vitro. Treating FSCs with dexamethasone before or after implantation further inhibited formation of fibromatosis nodules. Dexamethasone suppressed expression of TGF-β1 and pSmad2/3 by FSCs in vitro. TGF-β1 knockdown FSCs showed reducing myofibroblastic differentiation both in vitro and in vivo. Finally, addition of TGF-β1 abolished dexamethasone-mediated inhibition of myofibroblastic differentiation. Dexamethasone inhibits the myofibroblastic differentiated potential of FSCs both in vitro and in vivo through inhibition of TGF-β1 expression in FSCs. TGF-β1 plays a key role in myofibroblastic differentiation.
治疗肌肉骨骼纤维瘤仍然具有挑战性。纤维瘤的手术切除是标准疗法，但复发率仍然很高。皮质类固醇是一种抗纤维化化合物，已被用于治疗早期手掌纤维瘤，但机制尚不清楚。我们研究了皮质类固醇在纤维瘤结节的小鼠模型以及在培养的成纤维细胞中的抑制作用机制。使用定量逆转录/聚合酶链反应（PCR）分析和免疫荧光（IF）染色来检测地塞米松对成纤维细胞的肌成纤维分化的影响，无论是在体外还是在体内。使用 Western blot 分析检查转化生长因子-β1（TGF-β1）信号及其下游靶标。比较地塞米松处理前后成纤维细胞中 TGF-β1 的表达。此外，还通过 RNA 干扰（RNAi）在体外和体内检查了成纤维细胞中 TGF-β1 表达的抑制作用。地塞米松处理成纤维细胞可抑制体外成纤维细胞的肌成纤维分化。在植入前或植入后用地塞米松处理成纤维细胞可进一步抑制纤维瘤结节的形成。地塞米松可抑制成纤维细胞中 TGF-β1 和 pSmad2/3 的表达。体外 TGF-β1 敲低的成纤维细胞显示出减少的肌成纤维分化。最后，添加 TGF-β1 可消除地塞米松介导的肌成纤维分化抑制作用。地塞米松通过抑制成纤维细胞中 TGF-β1 的表达，在体外和体内均抑制成纤维细胞的肌成纤维分化潜能。TGF-β1 在肌成纤维分化中起关键作用。
