Skeletal defects are hallmark features of many extracellular matrix (ECM) and collagen-related disorders. However, a biological function in bone has never been defined for the highly evolutionarily conserved type IV collagen. Collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form α1α1α2 (IV) heterotrimers that represent a fundamental basement membrane constituent present in every organ of the body, including the skeleton. and mutations cause Gould syndrome, a variable and clinically heterogenous multisystem disorder generally characterized by the presence of cerebrovascular disease with ocular, renal, and muscular manifestations. We have previously identified elevated TGFβ signaling as a pathological insult resulting from mutations and demonstrated that reducing TGFβ signaling ameliorate ocular and cerebrovascular phenotypes in mutant mouse models of Gould syndrome. In this study, we describe the first characterization of skeletal defects in mutant mice that include a developmental delay in osteogenesis and structural, biomechanical and vascular alterations of mature bones. Using distinct mouse models, we show that allelic heterogeneity influences the presentation of skeletal pathology resulting from mutations. Importantly, we found that TGFβ target gene expression is elevated in developing bones from mutant mice and show that genetically reducing TGFβ signaling partially ameliorates skeletal manifestations. Collectively, these findings identify a novel and unsuspected role for type IV collagen in bone biology, expand the spectrum of manifestations associated with Gould syndrome to include skeletal abnormalities, and implicate elevated TGFβ signaling in skeletal pathogenesis in mutant mice.

中文翻译：

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Gould 综合征小鼠模型中的骨骼病理通过基因减少 TGFβ 信号传导部分缓解


骨骼缺陷是许多细胞外基质 （ECM） 和胶原蛋白相关疾病的标志性特征。然而，对于高度进化保守的 IV 型胶原蛋白，骨骼中的生物学功能从未被定义过。IV 型胶原 alpha 1 （COL4A1） 和 α 2 （COL4A2） 形成 α1α1α2 （IV） 异源三聚体，代表存在于身体每个器官（包括骨骼）中的基本基底膜成分。突变导致 Gould 综合征，这是一种多变的、临床异质性的多系统疾病，通常以脑血管疾病为特征，伴有眼部、肾脏和肌肉表现。我们之前已经将升高的 TGFβ 信号传导确定为突变导致的病理损伤，并证明减少 TGFβ 信号可改善 Gould 综合征突变小鼠模型中的眼脑血管表型。在这项研究中，我们描述了突变小鼠骨骼缺陷的首次特征，其中包括成骨发育迟缓以及成熟骨骼的结构、生物力学和血管改变。使用不同的小鼠模型，我们表明等位基因异质性会影响突变引起的骨骼病理的表现。重要的是，我们发现 TGFβ 靶基因表达在突变小鼠发育中的骨骼中升高，并表明遗传减少 TGFβ 信号传导部分改善骨骼表现。总的来说，这些发现确定了 IV 型胶原蛋白在骨骼生物学中的新颖且未被怀疑的作用，扩大了与 Gould 综合征相关的表现范围以包括骨骼异常，并暗示 TGFβ 信号升高在突变小鼠的骨骼发病机制中。