Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues
Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues
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DOI：
10.1359/jbmr.2002.17.7.1180
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发表时间：
2002-07-01
影响因子：
6.2
通讯作者：
Young, MF
中科院分区：
文献类型：
--
作者：
Corsi, A;Xu, T;Young, MF
核心蛋白聚糖（Decorin，dcn）和双糖链蛋白聚糖（biglycan，bgn）是富含亮氨酸的小分子蛋白聚糖（small leucine-rich proteoglycans，SLRP）家族的两个成员，分别是皮肤和骨骼中表达的主要蛋白聚糖。dcn基因的靶向破坏导致皮肤松弛和脆弱，而bgn基因的破坏导致骨骼生长和骨量减少，导致全身性骨质减少，特别是在老年动物中。在此，我们报告bgn缺乏导致骨、真皮和肌腱中胶原纤维结构异常，并导致真皮变薄但无明显皮肤脆性的“亚临床”皮肤表型。对bgn和dcn缺陷小鼠不同组织的超微结构比较研究显示，bgn和dcn缺陷对真皮中的胶原纤维结构有相似的影响，但对骨中的胶原纤维结构没有影响。新产生的bgn/dcn双敲除（KO）小鼠的超微结构和表型分析显示，dcn和bgn缺乏的影响是在真皮和骨中的协同作用。严重的皮肤脆性和明显的骨质减少是双KO动物的表型特征，其中在皮肤中也观察到早衰样变化。双基因敲除小鼠骨中骨胶原原纤维的超微结构分析揭示了基本原纤维几何形状的完全丧失，出现了明显的“锯齿状原纤维”形态。双KO动物的表型直接模拟人Ehlers-Danlos综合征（EDS）的罕见早老性变体，其中皮肤脆性、皮肤中的早老性变化（皮下组织减少）和骨质减少同时发生，这是由于与bgn和dcn核心蛋白连接的糖胺聚糖（GAG）受损。我们的数据表明，在胶原纤维形态的变化，让人想起那些发生在不同的频谱的人EDS的诱导bgn缺乏和dcn缺乏小鼠。单个SLRP缺陷的影响是组织特异性的，并且总体表型的表达取决于多个变量，包括不同组织中单个SLRP的表达水平和不同SLRP（和可能的其他大分子）之间在确定基质结构和功能性质方面的协同作用。
Decorin (dcn) and biglycan (bgn), two members of the family of small leucine-rich proteoglycans (SLRPs), are the predominant proteoglycans expressed in skin and bone, respectively. Targeted disruption of the dcn gene results in skin laxity and fragility, whereas disruption of the bgn gene results in reduced skeletal growth and bone mass leading to generalized osteopenia, particularly in older animals. Here, we report that bgn deficiency leads to structural abnormality in collagen fibrils in bone, dermis, and tendon, and to a "subclinical" cutaneous phenotype with thinning of the dermis but without overt skin fragility. A comparative ultrastructural study of different tissues from bgn- and dcn-deficient mice revealed that bgn and dcn deficiency have similar effects on collagen fibril structure in the dermis but not in bone. Ultrastructural and phenotypic analysis of newly generated bgn/dcn double-knockout (KO) mice revealed that the effects of dcn and bgn deficiency are additive in the dermis and synergistic in bone. Severe skin fragility and marked osteopenia characterize the phenotype of double-KO animals in which progeroid changes are observed also in the skin. Ultrastructural analysis of bone collagen fibrils in bone of double-KO mice reveals a complete loss of the basic fibril geometry with the emergence of marked "serrated fibril" morphology. The phenotype of the double-KO animal mimics directly the rare progeroid variant of human Ehlers-Danlos syndrome (EDS), in which skin fragility, progeroid changes in the skin (reduced hypodermis), and osteopenia concur as a result of impaired glycosaminoglycan (GAG) linking to bgn and dcn core proteins. Our data show that changes in collagen fibril morphology reminiscent of those occurring in the varied spectrum of human EDS are induced by both bgn deficiency and dcn deficiency in mice. The effects of an individual SLRP deficiency are tissue specific, and the expression of a gross phenotype depends on multiple variables including level of expression of individual SLRPs in different tissues and synergisms between different SLRPs (and likely other macromolecules) in determining matrix structure and functional properties.