激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SIONFH)是由于糖皮质激素使用不当或过度而引起的髋关节疾病,发病机制尚未统一,临床疗效亦不佳。当前,没有效果明确的药物可以延缓疾病进程,而中医药治疗SIONFH在...激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SIONFH)是由于糖皮质激素使用不当或过度而引起的髋关节疾病,发病机制尚未统一,临床疗效亦不佳。当前,没有效果明确的药物可以延缓疾病进程,而中医药治疗SIONFH在临床上取得一定疗效。即便如此,仍未能完整的从分子生物及细胞生物学角度阐明中药治疗SIONFH的作用机制。转化生长因子-β(TGF-β)/骨形态发生蛋白(BMP)/Smad信号通路的转导是防治SIONFH的研究热点之一,故该文阐明了该信号通路的转导机制以及与SIONFH的联系,检索了基于该通路治疗SIONFH的全部中药及复方并阐述其影响机制。基于中医对SIONFH的认识,现临床上使用补肝肾强筋骨以及活血祛瘀通络类的方药治疗SIONFH,且具有良好的疗效。中药通过调控该通路,可刺激骨髓间充质干细胞成骨分化,降低破骨细胞含量,减少脂肪生成,改善微循环,抗氧化损伤,促进股骨头内血管新生,从而促进股骨头损伤的修复。现基于TGF-β/BMP/Smad信号通路对中医药治疗SIONFH的研究进展做一综述,期许为中医药治疗SIONFH提供理论依据及参考。展开更多
AIM:To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells(HSCs) and whether Hes1 is regulated by transforming growth factor(TGF)/bone morphogenetic protein(BMP) signaling.METH...AIM:To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells(HSCs) and whether Hes1 is regulated by transforming growth factor(TGF)/bone morphogenetic protein(BMP) signaling.METHODS:Immunofluorescence staining was used to detect the expression of desmin,glial fibrillary acidic protein and the myofibroblastic marker α-smooth muscle actin(α-SMA) after freshly isolated,normal rat HSCs had been activated in culture for different numbers of days(0,1,3,7 and 10 d).The expression of α-SMA,collagen1α2(COL1α2),Notch receptors(Notch1-4),and the Notch target genes Hes1 and Hey1 were analyzed by reverse transcriptase-polymerase chain reaction.Luciferase reporter assays and Western blot were used to study the regulation of α-SMA,COL1α1,COL1α2 and Hes1 by NICD1,Hes1,CA-ALK3,and CA-ALK5 in HSC-T6 cells.Moreover,the effects of inhibiting Hes1 function in HSC-T6 cells using a Hes1 decoy were also investigated.RESULTS:The expression of Notch1 and Hes1 m RNAs was significantly down-regulated during the culture of freshly isolated HSCs.In HSC-T6 cells,Notch1 inhibited the promoter activities of α-SMA,COL1α1 and COL1α2.On the other hand,Hes1 enhanced the promoter activities of α-SMA and COL1α2,and this effect could be blocked by inhibiting Hes1 function with a Hes1 decoy.Furthermore,co-transfection of pc DNA3-CAALK3(BMP signaling activin receptor-like kinase 3) and pc DNA3.1-NICD1 further increased the expression of Hes1 compared with transfection of either vector alone in HSC-T6 cells,while pc DNA3-CA-ALK5(TGF-β signaling activin receptor-like kinase 5) reduced the effect of NICD1 on Hes1 expression.CONCLUSION:Selective interruption of Hes1 or maintenance of Hes1 at a reasonable level decreases the promoter activities of α-SMA and COL1α2,and these conditions may provide an anti-fibrotic strategy against hepatic fibrosis.展开更多
The hair follicle is a biological oscillator that alternates growth,regression,and rest phases driven by the sequential activation of the proliferation differentiation programs of resident stem cell populations.The ac...The hair follicle is a biological oscillator that alternates growth,regression,and rest phases driven by the sequential activation of the proliferation differentiation programs of resident stem cell populations.The activation of hair follicle stem cell niches and subsequent entry into the growing phase is mainly regulated by Wnt/β-catenin signalling,while regression and resting phases are mainly regulated by Tgf-β/Bmp/Smad activity.A major question still unresolved is the nature of the molecular switch that dictates the coordinated transition between both signalling pathways.Here we have focused on the role of Endoglin(Eng),a key co-receptor for members of the Tgf-β/Bmp family of growth factors.Using an Eng haploinsufficient mouse model,we report that Eng is required to maintain a correct follicle cycling pattern and for an adequate stimulation of hair follicle stem cell niches.We further report thatβ-catenin binds to the Eng promoter depending on Bmp signalling.Moreover,we show thatβ-catenin interacts with Smad4 in a Bmp/Eng-dependent context and both proteins act synergistically to activate Eng promoter transcription.These observations point to the existence of a growth/rest switching mechanism in the hair follicle that is based on an Eng-dependent feedback cross-talk between Wnt/β-catenin and Bmp/Smad signals.展开更多
文摘激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SIONFH)是由于糖皮质激素使用不当或过度而引起的髋关节疾病,发病机制尚未统一,临床疗效亦不佳。当前,没有效果明确的药物可以延缓疾病进程,而中医药治疗SIONFH在临床上取得一定疗效。即便如此,仍未能完整的从分子生物及细胞生物学角度阐明中药治疗SIONFH的作用机制。转化生长因子-β(TGF-β)/骨形态发生蛋白(BMP)/Smad信号通路的转导是防治SIONFH的研究热点之一,故该文阐明了该信号通路的转导机制以及与SIONFH的联系,检索了基于该通路治疗SIONFH的全部中药及复方并阐述其影响机制。基于中医对SIONFH的认识,现临床上使用补肝肾强筋骨以及活血祛瘀通络类的方药治疗SIONFH,且具有良好的疗效。中药通过调控该通路,可刺激骨髓间充质干细胞成骨分化,降低破骨细胞含量,减少脂肪生成,改善微循环,抗氧化损伤,促进股骨头内血管新生,从而促进股骨头损伤的修复。现基于TGF-β/BMP/Smad信号通路对中医药治疗SIONFH的研究进展做一综述,期许为中医药治疗SIONFH提供理论依据及参考。
基金Supported by National Natural Science Foundation of China,No.81170412,No.81070348 and No.81200307Health Department of Hubei Province of China,No.JX6C-26
文摘AIM:To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells(HSCs) and whether Hes1 is regulated by transforming growth factor(TGF)/bone morphogenetic protein(BMP) signaling.METHODS:Immunofluorescence staining was used to detect the expression of desmin,glial fibrillary acidic protein and the myofibroblastic marker α-smooth muscle actin(α-SMA) after freshly isolated,normal rat HSCs had been activated in culture for different numbers of days(0,1,3,7 and 10 d).The expression of α-SMA,collagen1α2(COL1α2),Notch receptors(Notch1-4),and the Notch target genes Hes1 and Hey1 were analyzed by reverse transcriptase-polymerase chain reaction.Luciferase reporter assays and Western blot were used to study the regulation of α-SMA,COL1α1,COL1α2 and Hes1 by NICD1,Hes1,CA-ALK3,and CA-ALK5 in HSC-T6 cells.Moreover,the effects of inhibiting Hes1 function in HSC-T6 cells using a Hes1 decoy were also investigated.RESULTS:The expression of Notch1 and Hes1 m RNAs was significantly down-regulated during the culture of freshly isolated HSCs.In HSC-T6 cells,Notch1 inhibited the promoter activities of α-SMA,COL1α1 and COL1α2.On the other hand,Hes1 enhanced the promoter activities of α-SMA and COL1α2,and this effect could be blocked by inhibiting Hes1 function with a Hes1 decoy.Furthermore,co-transfection of pc DNA3-CAALK3(BMP signaling activin receptor-like kinase 3) and pc DNA3.1-NICD1 further increased the expression of Hes1 compared with transfection of either vector alone in HSC-T6 cells,while pc DNA3-CA-ALK5(TGF-β signaling activin receptor-like kinase 5) reduced the effect of NICD1 on Hes1 expression.CONCLUSION:Selective interruption of Hes1 or maintenance of Hes1 at a reasonable level decreases the promoter activities of α-SMA and COL1α2,and these conditions may provide an anti-fibrotic strategy against hepatic fibrosis.
文摘The hair follicle is a biological oscillator that alternates growth,regression,and rest phases driven by the sequential activation of the proliferation differentiation programs of resident stem cell populations.The activation of hair follicle stem cell niches and subsequent entry into the growing phase is mainly regulated by Wnt/β-catenin signalling,while regression and resting phases are mainly regulated by Tgf-β/Bmp/Smad activity.A major question still unresolved is the nature of the molecular switch that dictates the coordinated transition between both signalling pathways.Here we have focused on the role of Endoglin(Eng),a key co-receptor for members of the Tgf-β/Bmp family of growth factors.Using an Eng haploinsufficient mouse model,we report that Eng is required to maintain a correct follicle cycling pattern and for an adequate stimulation of hair follicle stem cell niches.We further report thatβ-catenin binds to the Eng promoter depending on Bmp signalling.Moreover,we show thatβ-catenin interacts with Smad4 in a Bmp/Eng-dependent context and both proteins act synergistically to activate Eng promoter transcription.These observations point to the existence of a growth/rest switching mechanism in the hair follicle that is based on an Eng-dependent feedback cross-talk between Wnt/β-catenin and Bmp/Smad signals.
