Charbonneau Noe L, Ono Robert N, Corson Glen M, Keene Douglas R, Sakai Lynn Y
Shriners Hospital for Children, and the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon.
Birth Defects Res C Embryo Today. 2004 Mar;72(1):37-50. doi: 10.1002/bdrc.20000.
Growth factors, potent regulators of cell differentiation, tissue morphogenesis, tissue homeostasis, and cellular response to injury, reside in the extracellular matrix. Genetic evidence in humans and mice as well as biochemical data implicate fibrillins and LTBPs in the extracellular control of TGFbeta and BMP signaling. Fibrillins and LTBPs form tissue-specific and temporally regulated microfibril networks. In the developing embryo, three fibrillins and four LTBPs contribute molecular heterogeneity to microfibril networks, and provide different templates upon which TGFbeta-related growth factors can be positioned. By accommodating this molecular heterogeneity, microfibril architecture can orchestrate a variety of different signals in very specific tissue locations. Human fibrillinopathies display a broad phenotypic spectrum from tall to short stature, from hypermobile joints to joint contractures and stiffness, and from severe to mild or no cardiovascular manifestations. A spectrum of growth factor dysregulation may be caused by differential effects of mutations in fibrillins on microfibril architecture, thus altering appropriate targeting or positioning of growth factors within microfibril networks. Growth factor dysregulation may help to explain the broad phenotypic spectrum of the fibrillinopathies.
生长因子是细胞分化、组织形态发生、组织稳态及细胞对损伤反应的强效调节因子，存在于细胞外基质中。人和小鼠的遗传学证据以及生化数据表明，原纤蛋白和潜伏性转化生长因子结合蛋白参与转化生长因子β（TGFβ）和骨形态发生蛋白（BMP）信号的细胞外调控。原纤蛋白和潜伏性转化生长因子结合蛋白形成组织特异性且受时间调控的微原纤维网络。在发育中的胚胎里，三种原纤蛋白和四种潜伏性转化生长因子结合蛋白为微原纤维网络贡献分子异质性，并提供不同的模板，TGFβ相关生长因子可定位其上。通过适应这种分子异质性，微原纤维结构能够在非常特定的组织位置协调各种不同的信号。人类原纤蛋白病表现出广泛的表型谱，从身材高大到矮小，从关节活动过度到关节挛缩和僵硬，以及从严重到轻度或无心血管表现。原纤蛋白突变对微原纤维结构的不同影响可能导致一系列生长因子失调，从而改变生长因子在微原纤维网络内的适当靶向或定位。生长因子失调可能有助于解释原纤蛋白病广泛的表型谱。
