Poon Raymond, Li Catherine, Alman Benjamin A
Division of Orthopaedic Surgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G1X8, Canada.
Clin Orthop Relat Res. 2009 May;467(5):1180-5. doi: 10.1007/s11999-008-0692-7. Epub 2009 Jan 24.
The contracted tissues from clubfeet resemble tissues from other fibroproliferative disorders such as palmar fibromatosis. Beta-catenin-mediated signaling is a crucial pathway controlling the fibroproliferative response in many fibroproliferative disorders. To determine if beta-catenin signaling plays a role in clubfoot, contracted and less contracted tissues from clubfeet were studied using Western analysis to determine the protein level of beta-catenin. Primary cell cultures were established from these tissues, and they were treated with either lithium to increase beta-catenin or Dickkopf-1 to inhibit beta-catenin. RNA was extracted from the cells and analyzed to determine how beta-catenin regulates expression of Type III collagen, an extracellular matrix protein upregulated in contracted clubfoot tissue. There was a more than twofold increase in beta-catenin protein in the contracted tissues. Treatment with either lithium or Dickkopf-1 showed Type III collagen RNA expression positively correlated with the protein level of beta-catenin. These data support the concept that beta-catenin-mediated signaling plays an important role regulating contracture in clubfeet. Because pharmacologic agents are under development to block this signaling pathway, such drugs could be used in cases of severe stiffness to improve range of motion or to decrease the need for radical surgical approaches.
马蹄内翻足的挛缩组织类似于其他纤维增生性疾病（如掌纤维瘤病）的组织。β-连环蛋白介导的信号传导是控制许多纤维增生性疾病中纤维增生反应的关键途径。为了确定β-连环蛋白信号传导在马蹄内翻足中是否起作用，研究人员使用蛋白质免疫印迹法研究了马蹄内翻足的挛缩组织和挛缩程度较轻的组织，以确定β-连环蛋白的蛋白质水平。从这些组织中建立了原代细胞培养物，并用锂盐处理以增加β-连环蛋白，或用Dickkopf-1处理以抑制β-连环蛋白。从细胞中提取RNA并进行分析，以确定β-连环蛋白如何调节III型胶原蛋白的表达，III型胶原蛋白是一种在马蹄内翻足挛缩组织中上调的细胞外基质蛋白。挛缩组织中β-连环蛋白的蛋白质水平增加了两倍多。用锂盐或Dickkopf-1处理均显示III型胶原蛋白RNA表达与β-连环蛋白的蛋白质水平呈正相关。这些数据支持了β-连环蛋白介导的信号传导在调节马蹄内翻足挛缩中起重要作用的观点。由于正在开发阻断该信号通路的药物，此类药物可用于严重僵硬的病例，以改善活动范围或减少激进手术方法的需求。
