Prolonged β-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds
Prolonged β-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds
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DOI：
10.1038/labinvest.3700237
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发表时间：
2005-03-01
影响因子：
5
通讯作者：
Alman, BA
中科院分区：
文献类型：
--
作者：
Cheon, S;Poon, R;Alman, BA
在伤口愈合的增殖期期间积累的以及存在于增生性伤口中的间充质细胞与来自纤维增殖性损伤的细胞具有细胞学相似性，在纤维增殖性损伤中存在β-连环蛋白介导的转录的激活。将先前活检的重新切除伤口和来自增生性皮肤伤口的样本与正常组织一起进行研究。在正常伤口愈合过程中，β-连环蛋白水平有所增加，在损伤后 4 周达到峰值，并在 12 周时恢复到基线水平。增生性伤口表现出 β-连环蛋白升高持续时间较长，在初次损伤后持续 2 年以上。已知在伤口愈合的增殖期上调的基因（α-平滑肌肌动蛋白和三型胶原）的表达水平与β-连环蛋白水平相关。糖原合成酶激酶-3-β（一种对β-连环蛋白不稳定很重要的激酶）的磷酸化水平与β-连环蛋白蛋白水平相关。 β-连环蛋白靶基因（MMP-7和FN）的表达以及原代细胞培养物中tcf报告基因的激活证明了β-连环蛋白在这些伤口中具有转录活性。 β-连环蛋白稳定可增加体外成纤维细胞的细胞增殖和运动性，并且在正常伤口愈合的增殖阶段其短暂升高期间可能具有类似的功能。在增生性伤口中，β-连环蛋白失调，使间充质细胞维持在长时间的增殖状态。因此，β-连环蛋白可能在愈合过程中在间充质细胞中发挥核心作用，并且是伤口愈合障碍的有吸引力的治疗靶点。
Mesenchymal cells that accumulate during the proliferative phase of wound healing and that are present in hyperplastic wounds share cytologic similarities with the cells from fibroproliferative lesions in which there is activation of beta- catenin- mediated transcription. Re- excision wounds from a previous biopsy and samples from hyperplastic cutaneous wounds were studied along with normal tissues. During normal wound healing, there was an increase in beta- catenin protein level, peaking 4 weeks following the insult and returning towards baseline level by 12 weeks. Hyperplastic wounds exhibited a prolonged duration of elevated b- catenin, lasting more than 2 years following the initial injury. The level of expression of genes known to be upregulated in the proliferative phase of wound healing ( alpha- smooth muscle actin and type three collagen), correlated with beta- catenin protein level. The phosphorylation level of glycogen synthase kinase- 3- beta, a kinase important for beta- catenin protein destabilization, correlated with beta- catenin protein level. beta- Catenin was transcriptionally active in these wounds as demonstrated by the expression of the beta- catenin target genes ( MMP- 7 and FN) and by activation of a tcf-reporter in primary cell cultures. beta- catenin stabilization increases cell proliferation and motility in fibroblasts in vitro, and likely has a similar function during its transient elevation in the proliferative phase of normal wound healing. In hyperplastic wounds, there is dysregulation of beta- catenin, maintaining the mesenchymal cells in a prolonged proliferative state. As such, beta- catenin likely plays a central role in mesenchymal cells during the healing process, and is an appealing therapeutic target for disorders of wound healing.