Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein
Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein
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DOI：
10.1086/302829
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发表时间：
2000-03-01
影响因子：
9.8
通讯作者：
Weksberg, R
中科院分区：
文献类型：
--
作者：
Hinek, A;Smith, AC;Weksberg, R
科斯特洛综合征的特征是智力低下、皮肤松弛、面部粗糙、骨骼畸形、心肌病以及易患多种恶性肿瘤。Costello综合征的遗传起源尚未确定。通过免疫组织化学和[H-3]-valine的代谢标记，我们已经证实，从Costello综合征患者获得的培养的皮肤成纤维细胞不能组装弹性纤维，尽管有足够的原弹性蛋白合成和微纤维支架的正常沉积。我们发现，这些成纤维细胞产生弹性纤维的障碍与67-kD弹性蛋白结合蛋白(EBP)的功能缺陷有关，EBP通常是陪伴原弹性蛋白通过分泌途径及其细胞外组装所必需的。用放射性丝氨酸对67-kD的EBP进行代谢脉冲标记和进一步追逐该示踪物表明，正常成纤维细胞和Costello综合征患者的成纤维细胞最初合成了相同数量的这种蛋白质；然而，Costello综合征患者的成纤维细胞很快将其丢失到条件培养液中。由于EBP和原弹性蛋白之间的正常联系在接触含半乳糖的部分时会被破坏，而Costello综合征患者的成纤维细胞显示含有硫酸软骨素的蛋白多糖(CD44和Biglycan)异常积聚，我们推测硫酸软骨素可能是导致EBP从Costello细胞中脱落并进而导致其弹力生成受损的原因。进一步支持这一事实的事实是，暴露于软骨素酶ABC，一种能够降解硫酸软骨素的酶，恢复了科斯特洛综合征患者成纤维细胞正常产生弹性纤维的能力。我们还提出证据表明，Costello综合征患者成纤维细胞中EBP的丢失与异常高的细胞增殖率有关。
Costello syndrome is characterized by mental retardation, loose skin, coarse face, skeletal deformations, cardiomyopathy, and predisposition to numerous malignancies. The genetic origin of Costello syndrome has not yet been defined. Using immunohistochemistry and metabolic labeling with [H-3]-valine, we have established that cultured skin fibroblasts obtained from patients with Costello syndrome did not assemble elastic fibers, despite an adequate synthesis of tropoelastin and normal deposition of the microfibrillar scaffold. We found that impaired production of elastic fibers by these fibroblasts is associated with a functional deficiency of the 67-kD elastin-binding protein (EBP), which is normally required to chaperone tropoelastin through the secretory pathways and to its extracellular assembly. Metabolic pulse labeling of the 67-kD EBP with radioactive serine and further chase of this tracer indicated that both normal fibroblasts and fibroblasts from patients with Costello syndrome initially synthesized comparable amounts of this protein; however, the fibroblasts from Costello syndrome patients quickly lost it into the conditioned media. Because the normal association between EBP and tropoelastin can be disrupted on contact with galactosugarbearing moieties, and the fibroblasts from patients with Costello syndrome revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible for shedding EBP from Costello cells and in turn for their impaired elastogenesis. This was further supported by the fact that exposure to chondroitinase ABC, an enzyme capable of chondroitin sulfate degradation, restored normal production of elastic fibers by fibroblasts from patients with Costello syndrome. We also present evidence that loss of EBP from fibroblasts of Costello syndrome patients is associated with an unusually high rate of cellular proliferation.