成骨形态发生蛋白在进行性骨化性纤维发育不良中的过表达。

Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva.

作者信息

Shafritz A B, Shore E M, Gannon F H, Zasloff M A, Taub R, Muenke M, Kaplan F S

机构信息

Department of Orthopaedic Surgery, University of Pennsylvania School ofMedicine, Philadelphia 19104, USA.

出版信息

N Engl J Med. 1996 Aug 22;335(8):555-61. doi: 10.1056/NEJM199608223350804.

DOI:10.1056/NEJM199608223350804

PMID:8678932

Abstract

BACKGROUND

Fibrodysplasia ossificans progressiva is a heritable disorder of connective tissue characterized by congenital malformation of the great toes and postnatal formation of ectopic bone. Although the disorder was first described more than 300 years ago, the genetic defect and pathophysiology remain unknown. Bone morphogenetic proteins are potent bone-inducing morphogens that participate in the developmental organization of the skeleton, and increased production of one or more of these proteins has been proposed as the cause of fibrodysplasia ossificans progressiva.

METHODS

We studied lymphoblastoid cell lines established from peripheral-blood mononuclear cells of patients with fibrodysplasia ossificans progressiva and fibroblast-like cell lines derived from lesional and nonlesional tissue. We used Northern blot analysis and ribonuclease protection assays to measure the expression of messenger RNA (mRNA) of bone morphogenetic proteins 1 to 7 and immunohistochemical analysis to examine protein expression.

RESULTS

Among the bone morphogenetic proteins and mRNAs examined, only bone morphogenetic protein 4 and its mRNA were present in increased levels in cells derived from an early fibroproliferative lesion in a patient with fibrodysplasia ossificans progressiva. Bone morphogenetic protein 4 mRNA was expressed in lymphoblastoid cell lines from 26 of 32 patients with fibrodysplasia ossificans progressiva but from only 1 of 12 normal subjects (P<0.001). Bone morphogenetic protein 4 and its mRNA were detected in the lymphoblastoid cell lines from a man with fibrodysplasia ossificans progressiva and his three affected children (two girls and a boy), but not from the children's unaffected mother. No other bone morphogenetic proteins were detected.

CONCLUSIONS

Overexpression of a potent bone-inducing morphogen (bone morphogenetic protein 4) in lymphocytes is associated with the disabling ectopic osteogenesis of fibrodysplasia ossificans progressiva.

摘要

背景

进行性骨化性纤维发育不良是一种结缔组织遗传性疾病，其特征为大脚趾先天性畸形以及出生后异位骨形成。尽管该疾病在300多年前就首次被描述，但遗传缺陷和病理生理学仍不清楚。骨形态发生蛋白是强大的骨诱导形态发生素，参与骨骼的发育组织，并且一种或多种这些蛋白的产生增加被认为是进行性骨化性纤维发育不良的病因。

方法

我们研究了从进行性骨化性纤维发育不良患者外周血单个核细胞建立的淋巴母细胞系以及来自病变和非病变组织的成纤维细胞样细胞系。我们使用Northern印迹分析和核糖核酸酶保护试验来测量骨形态发生蛋白１至７的信使核糖核酸（mRNA）表达，并使用免疫组织化学分析来检测蛋白表达。

结果

在所检测的骨形态发生蛋白和mRNA中，只有骨形态发生蛋白4及其mRNA在一名进行性骨化性纤维发育不良患者早期纤维增殖性病变来源的细胞中水平升高。骨形态发生蛋白4 mRNA在32例进行性骨化性纤维发育不良患者中的26例的淋巴母细胞系中表达，但在12名正常受试者中的仅1例中表达（P<0.001）。在一名进行性骨化性纤维发育不良男性患者及其三个患病子女（两个女孩和一个男孩）的淋巴母细胞系中检测到骨形态发生蛋白4及其mRNA，但在子女未患病的母亲中未检测到。未检测到其他骨形态发生蛋白。