Expression and activation of the BMP-signaling components in human fracture nonunions
Expression and activation of the BMP-signaling components in human fracture nonunions
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DOI：
10.2106/00004623-200211000-00001
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发表时间：
2002-11-01
影响因子：
5.3
通讯作者：
Helfet, DL
中科院分区：
文献类型：
--
作者：
Kloen, P;Doty, SB;Helfet, DL
背景：骨形态发生蛋白（BMPS）促进骨愈合的潜在用途引起了骨科医生的极大兴趣。尽管人们越来越了解局部存在 BMP（无论是内源性还是外源性）导致骨形成的复杂机制，但关于内源性 BMP、其受体或参与其信号转导的其他分子（如 Smad1）在骨折不愈合过程中是否存在或消失的信息有限。本研究的目的是通过免疫组织化学分析确定骨折不愈合过程中 BMP、BMP 受体或 Smad1 是否从组织中消失。 方法：纳入 21 名延迟愈合（4 名患者）或骨不连（17 名患者）的患者（平均年龄，61 岁；范围，30 至 85 岁）。延迟愈合或不愈合的平均持续时间为 22 个月（范围为 3.5 至 120 个月）。通过免疫组织化学分析，我们研究了 BMP-2、BMP-4 和 BMP-7 及其受体 BMPR-IA、BMPR-IB 和 BMPR-II 以及 pSmad1 的定位。通过使用 pSmad1 抗体，我们还研究了表达的 BMP 受体是否被激活。结果：21 名患者中的 17 名 (81%) 证实了所有 7 种 BMP 信号成分的免疫组织化学定位。其余四名患者缺乏一种或多种成分。新形成的骨区域的阳性染色细胞比例最高，而远离骨形成的区域的染色通常会减少。然而，即使在致密纤维组织区域和缺乏新形成骨骼的标本中，免疫染色仍然存在。染色模式显示 BMP-2、BMP-4 和 BMP-7 蛋白与 BMP 受体共定位。 pSmad1 的存在标志着 BMP 受体的激活状态，这意味着 BMP 信号在细胞内转导。 结论和临床相关性：在本研究中，长期不愈合被发现有持续 BMP 信号传导的证据。该组患者的 BMP、BMP 受体和 pSmad1 免疫染色谱存在异质性。本研究结果不支持延迟愈合和不愈合部位缺乏 BMP 信号成分表达和激活的概念。
Background: The potential use of bone morphogenetic proteins (BMPS) to promote bone-healing is of great interest to orthopaedic surgeons. Although the complex mechanism leading from the local presence of BMP (whether endogenous or exogenous) to bone formation is increasingly understood, limited information is available as to whether endogenous BMPs, their receptors, or other molecules involved in their signal transduction, such as Smad1, are present or disappear during the development of fracture nonunions. The purpose of the present study was to determine, by immunohistochemical analysis, whether BMPs, BMP receptors, or Smad1 disappear from tissues during the development of a fracture nonunion.Methods: Twenty-one patients (average age, sixty-one years; range, thirty to eighty-five years) with a delayed union (four patients) or a nonunion (seventeen patients) were included. The average duration of the delayed union or nonunion was twenty-two months (range, 3.5 to 120 months). With use of immunohistochemical analysis, we studied the localization of BMP-2, BMP-4, and BMP-7 and their receptors BMPR-IA, BMPR-IB, and BMPR-II as well as pSmad1. With use of a pSmad1 antibody, we also studied whether the BMP receptors that were expressed were activated.Results: The immunohistochemical localization of all seven BMP-signaling components was demonstrated in seventeen (81%) of the twenty-one patients. The remaining four patients lacked one or more of the components. Areas of newly formed bone had the highest percentage of positively staining cells, with the staining generally decreasing in areas remote from bone formation. However, even in areas of dense fibrous tissue and in specimens that lacked newly formed bone, immunostaining was still present. The staining patterns showed colocalization of the BMP-2, BMP-4, and BMP-7 proteins with the BMP receptors. The presence of pSmad1 signified the activated state of the BMP receptors, which implies that the BMP signal is transduced inside the cell.Conclusions and Clinical Relevance: In the present study, nonunions of long duration were noted to have evidence of ongoing BMP-signaling. The profiles of BMP, BMP-receptor, and pSmad1 immunostaining were heterogeneous in this group of patients. The concept that the expression and activation of BMP-signaling components are lacking at the site of delayed unions and nonunions was not supported by the results of the present study.