Matrix Biology最新文献_第4页

Drosophila Col4a1 Glycine mutations highlight allelic heterogeneity and mechanistic pleiotropy 果蝇Col4a1甘氨酸突变突出了等位基因异质性和机制多效性。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-07-22 DOI: 10.1016/j.matbio.2025.07.005

Angus Nichols, Besaiz J. Sánchez-Sánchez, Stefania Marcotti, María-del-Carmen Díaz-de-la-Loza, Leonel C. Menezes, Tingfei Wang, Robert M. Johnson, Brian M. Stramer

Collagen IV (Col4) is a heterotrimer containing a triple helical domain broken up by short interruptions. Mutation of Glycine residues within the Glycine-X-Y triple helical repeat leads to genetically dominant disease in humans that affects multiple organ systems. Mouse and cell culture-based models have revealed allelic heterogeneity, resulting in a range of Col4 secretion defects depending on the position of the mutation. However, genetic background also affects phenotypic severity, making it challenging to understand the precise underlying molecular mechanisms driving disease. Here, we characterize an allelic series of dominant temperature-sensitive Drosophila Glycine mutations to identify the potential molecular mechanisms driving phenotypic heterogeneity. Analysis of developmental viability at the non-permissive temperature revealed that mutations show a range of developmental lethality that is not correlated with their position within the triple helix nor with the degree of Col4 secretion defect. Backcrossing the series of fly lines led to increased lethality for almost all alleles, highlighting the presence of genetic modifiers, which paradoxically led to a reduction in secretion defects; this further suggests that defective secretion cannot explain the allelic heterogeneity in mutant viability. Analysis of the Col4 network surrounding the central nervous system (CNS) revealed that Glycine mutations can also affect basement membrane (BM) structure and alter its mechanical properties. Additionally, fluorescent tagging of a Glycine mutant variant showed that the mutated trimer is sufficiently secreted and can be incorporated into the network to dominantly affect BM organization. These data reveal that Col4 Glycine mutations can cause both secretion and direct BM network defects, suggesting that Col4-related pathologies may be mechanistically pleiotropic.

胶原IV （Col4）是一种含有三螺旋结构域的异源三聚体，该结构域由短中断断开。甘氨酸- x - y三螺旋重复序列中甘氨酸残基的突变导致人类遗传显性疾病，影响多器官系统。基于小鼠和细胞培养的模型揭示了等位基因的异质性，导致Col4分泌缺陷的范围取决于突变的位置。然而，遗传背景也会影响表型的严重程度，这使得理解驱动疾病的精确潜在分子机制具有挑战性。在这里，我们描述了一系列显性温度敏感的果蝇甘氨酸突变的等位基因，以确定驱动表型异质性的潜在分子机制。在非允许温度下的发育活力分析表明，突变显示出一系列的发育致死率，这与它们在三螺旋中的位置无关，也与Col4分泌缺陷的程度无关。蝇系系列的回交导致几乎所有等位基因的致死率增加，突出了遗传修饰的存在，这矛盾地导致了分泌缺陷的减少；这进一步表明分泌缺陷不能解释突变体活力的等位基因异质性。对中枢神经系统（CNS）周围Col4网络的分析表明，甘氨酸突变也可以影响基底膜（BM）结构并改变其力学性能。此外，甘氨酸突变变体的荧光标记表明，突变的三聚体分泌充足，可以被纳入网络，主要影响BM组织。这些数据表明Col4甘氨酸突变既可以引起分泌缺陷，也可以引起直接的BM网络缺陷，这表明Col4相关的病理可能是多效性的。

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引用次数: 0

ECM proteins shape topographical patterns in the basement membrane of Drosophila wing discs ECM蛋白在果蝇翅盘基底膜中形成地形模式

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-07-15 DOI: 10.1016/j.matbio.2025.06.003

K. Yanín Guerra Santillán, Christian Dahmann, Elisabeth Fischer-Friedrich

The basal surface of epithelial tissues is attached to a thin network of macromolecules known as the basement membrane. The core components of the basement membrane — Collagen IV, Laminin, Perlecan, and Nidogen — are conserved extracellular matrix (ECM) proteins across species. However, the topography of basement membranes and the contribution of individual core components to its establishment remain poorly understood. Here, we used AFM-aided PeakForce tapping to analyze the topography of the basement membrane of Drosophila larval wing discs. We identified a self-affine surface topography, appearing structurally similar across multiple scales. Further, the topography is characterized by thin fiber-like structures that are intermittently aligned with a preferred orientation along the anterior-posterior axis. During larval development, the amplitude of surface patterns overall decreases, whereas the abundance of basement membrane components increases. Using targeted knockdown experiments, we show that Collagen IV is essential for the formation of fiber-like structures, while Laminin and Collagen IV appear to smooth or level out large-scale groove-like patterns. In contrast, Nidogen contributes to the maintenance of these grooves, and Perlecan increases surface pattern amplitudes at all length scales. Our findings reveal distinct topographical features in the basement membrane, whose amplitude and organization depend on its specific molecular composition.

上皮组织的基底表面附着着一层称为基底膜的大分子薄网络。基底膜的核心成分-胶原IV，层粘连蛋白，Perlecan和Nidogen -是跨物种保守的细胞外基质（ECM）蛋白。然而，基底膜的地形和单个核心成分对其建立的贡献仍然知之甚少。在此，我们使用afm辅助PeakForce攻丝对果蝇幼虫翅盘基底膜的形貌进行了分析。我们确定了一个自仿射表面形貌，在多个尺度上出现结构相似。此外，地形的特征是薄的纤维状结构，沿着前后轴间歇性地以首选方向排列。在幼虫发育过程中，表面图案的幅度总体下降，而基底膜成分的丰度增加。通过靶向敲除实验，我们发现胶原蛋白IV对于纤维样结构的形成至关重要，而层粘连蛋白和胶原蛋白IV似乎可以平滑或平整大规模的沟槽样结构。相比之下，氮气有助于维持这些凹槽，而Perlecan则增加了所有长度尺度上的表面图案振幅。我们的发现揭示了基底膜的独特地形特征，其振幅和组织取决于其特定的分子组成。

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引用次数: 0

Role of extracellular space and matrix remodeling in cardiac amyloidosis 细胞外空间和基质重塑在心脏淀粉样变性中的作用

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-07-14 DOI: 10.1016/j.matbio.2025.07.004

Francesca Lavatelli , Loredana Marchese , Palma Patrizia Mangione , Sara Raimondi , Diana Canetti , Guglielmo Verona , Lucia Venneri , Eloisa Arbustini , Laura Obici , Alessandra Corazza , Vittorio Bellotti , Sofia Giorgetti

The hallmark of amyloid diseases is deposition of misfolded proteins as amyloid fibrils in the interstitium of target organs. Amyloid deposits surround cells, distorting the micro and macro-architecture of the extracellular space and profoundly changing the physical and molecular properties of this compartment. In the heart, extracellular matrix (ECM) remodeling has a profound impact on the mechanical properties of this target organ and on the physiology and metabolism of resident cells. This review critically summarizes the available knowledge on ECM alterations in cardiac amyloidosis, with the goal of providing an overview on how biochemical, biophysical and anatomical modifications are interrelated, and how ECM remodeling participates in the pathophysiology of this unique type of cardiopathy.

淀粉样蛋白疾病的标志是错误折叠的蛋白作为淀粉样原纤维沉积在靶器官间质中。淀粉样蛋白沉积在细胞周围，扭曲了细胞外空间的微观和宏观结构，并深刻地改变了细胞外空间的物理和分子特性。在心脏中，细胞外基质（extracellular matrix， ECM）重构对靶器官的力学特性以及常驻细胞的生理和代谢具有深远的影响。这篇综述批判性地总结了心肌淀粉样变性中ECM改变的现有知识，目的是概述生化，生物物理和解剖改变是如何相互关联的，以及ECM重塑如何参与这种独特类型的心脏病的病理生理学。

引用次数: 0

Building basement membranes with computational approaches 用计算方法构建基底膜。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-07-09 DOI: 10.1016/j.matbio.2025.07.001

Alana Stevenson Harris , Rachel Lennon , Jean-Marc Schwartz

Basement membranes (BMs) are dense extracellular matrix scaffolds that support cells. Their composition, structure and dynamic regulation are vital for tissue health and altered in human disease. The expansion of experimental and analytical techniques has generated large multiomic datasets that include BM components; however, the organising principles of BM component assembly and the regulation of BMs remain poorly understood. There are over 160 curated BM proteins, including core, ubiquitous components such as type IV collagen and laminin isoforms, as well as tissue-restricted components, and there is increasing experimental evidence of BM protein-protein interactions. Here we describe and compare multiomic, protein-protein interaction, and BM curation databases and discuss the application of systems biology approaches including network analysis, Boolean networks and Ordinary Differential Equations to integrate data and model BM organisation. Applying computational modelling strategies to BM datasets may reveal unknown organising principles of BM assembly and regulation and predict mechanisms of dysregulation in BM-associated diseases.

基底膜（BMs）是致密的细胞外基质支架，支持细胞。它们的组成、结构和动态调节对组织健康和人类疾病的改变至关重要。实验和分析技术的扩展产生了包括BM成分的大型多组数据集；然而，BM组件组装的组织原则和BM的调节仍然知之甚少。目前有超过160种BM蛋白，包括核心成分，普遍存在的成分，如IV型胶原蛋白和层粘连蛋白异构体，以及组织限制性成分，并且越来越多的实验证据表明BM蛋白与蛋白质相互作用。在这里，我们描述和比较多组学、蛋白质-蛋白质相互作用和BM管理数据库，并讨论系统生物学方法的应用，包括网络分析、布尔网络和常微分方程，以整合数据和建模BM组织。将计算建模策略应用于脑基数据集可以揭示脑基组装和调节的未知组织原理，并预测脑基相关疾病的失调机制。

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引用次数: 0

Around the collagen triple helix: an introduction to studying associated genetic and acquired diseases 围绕胶原蛋白三螺旋：介绍研究相关的遗传和获得性疾病。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-07-07 DOI: 10.1016/j.matbio.2025.07.003

Sergei P. Boudko

The triple helix structure of collagen is the most abundant motif found in our bodies. It is believed to have emerged during the transition from unicellular to multicellular animal organisms, known as metazoans, and has evolved into various proteins that contribute to the development and function of diverse animal tissues, organs, and systems. Once synthesized, these collagenous proteins undergo post-translational modifications and proper folding inside the cell, after which they primarily function outside the cell. Over 80 collagenous proteins are categorized into two main groups: collagens and collagen-like proteins. However, the distinction between these groups is not clearly defined. Within these categories, there are various types of proteins, including soluble proteins, transmembrane proteins, and those that form the extracellular matrix. Multiple genetic diseases highlight the significance of collagenous proteins, which can be affected by defects in their primary structure, post-translational modifications, or complete loss. While fixing the gene defect may seem like a straightforward solution, we currently lack the capability to do so. Moreover, acquired diseases caused or accompanied by adverse processes in the collagen triple helix are generally not suitable for gene therapy at all. Understanding the pathogenicity of a defective polypeptide chain can provide valuable insights into strategies for mitigating negative consequences for both genetic and acquired diseases. This review highlights the current state of research in the collagen triple helix field, offering insights into how to study specific defects and deepen our understanding of their underlying pathogenic mechanisms.

胶原蛋白的三螺旋结构是我们体内发现的最丰富的基序。它被认为是在从单细胞动物有机体向多细胞动物有机体过渡的过程中出现的，被称为后生动物，并已进化成各种蛋白质，这些蛋白质有助于各种动物组织、器官和系统的发育和功能。一旦合成，这些胶原蛋白在细胞内进行翻译后修饰和适当折叠，之后它们主要在细胞外发挥作用。超过80种胶原蛋白被分为两大类：胶原蛋白和胶原样蛋白。然而，这些群体之间的区别并没有明确界定。在这些类别中，有各种类型的蛋白质，包括可溶性蛋白质，跨膜蛋白质和那些形成细胞外基质的蛋白质。多种遗传疾病突出了胶原蛋白的重要性，胶原蛋白可能受到其初级结构缺陷、翻译后修饰或完全丢失的影响。虽然修复基因缺陷似乎是一个直截了当的解决方案，但我们目前缺乏这样做的能力。此外，由胶原蛋白三螺旋不良过程引起或伴随的获得性疾病，一般根本不适合进行基因治疗。了解缺陷多肽链的致病性可以为减轻遗传和获得性疾病的负面后果提供有价值的见解。本文综述了胶原蛋白三螺旋领域的研究现状，为如何研究特定缺陷和加深对其潜在致病机制的理解提供了新的见解。

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引用次数: 0

Collagen IV biosynthesis: Intracellular choreography of post-translational modifications 胶原IV型生物合成：翻译后修饰的细胞内编排。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-07-04 DOI: 10.1016/j.matbio.2025.07.002

Yoshihiro Ishikawa , Rachel Lennon , Federico Forneris , Johanna Myllyharju , Antti M. Salo

Collagen IV, an essential and evolutionarily conserved component of basement membranes, is one of the most extensively post-translationally modified proteins. Despite substantial research on fibrillar collagen biosynthesis, our understanding of collagen IV biosynthesis, including its post-translational modifications (PTMs), remains limited. Most PTMs occur intracellularly, primarily within the endoplasmic reticulum (ER). In this review, we examine the molecular ensemble that orchestrates collagen IV biosynthesis in the ER, highlighting the complex interplay between prolyl and lysyl hydroxylases, glycosyltransferases, and molecular chaperones. Furthermore, we discuss how defects in collagen IV and its PTMs contribute to various human pathologies, including Gould and Alport syndromes, fibrosis, and cancer. Understanding collagen IV PTMs is crucial for elucidating the molecular basis of these diseases and improving targeted treatments. By reviewing our knowledge of collagen IV biosynthesis, we illustrate how this evolutionarily conserved yet highly specialized molecular biosynthesis ensemble supports the diverse functions of collagen IV in health and disease.

IV型胶原是一种重要的、进化上保守的基底膜成分，是最广泛的翻译后修饰蛋白之一。尽管对纤维性胶原的生物合成进行了大量的研究，但我们对IV型胶原的生物合成，包括其翻译后修饰（PTMs）的了解仍然有限。大多数PTMs发生在细胞内，主要发生在内质网（ER）内。在这篇综述中，我们研究了内质网中协调IV型胶原生物合成的分子集合，强调了脯氨酸和赖氨酸羟化酶、糖基转移酶和分子伴侣之间的复杂相互作用。此外，我们还讨论了IV型胶原及其PTMs中的缺陷如何导致各种人类病理，包括Gould和Alport综合征、纤维化和癌症。了解胶原IV型PTMs对于阐明这些疾病的分子基础和改善靶向治疗至关重要。通过回顾我们对IV型胶原蛋白生物合成的了解，我们说明了这种进化上保守但高度特化的分子生物合成合体如何支持IV型胶原蛋白在健康和疾病中的多种功能。

{"title":"Collagen IV biosynthesis: Intracellular choreography of post-translational modifications","authors":"Yoshihiro Ishikawa , Rachel Lennon , Federico Forneris , Johanna Myllyharju , Antti M. Salo","doi":"10.1016/j.matbio.2025.07.002","DOIUrl":"10.1016/j.matbio.2025.07.002","url":null,"abstract":"<div><div>Collagen IV, an essential and evolutionarily conserved component of basement membranes, is one of the most extensively post-translationally modified proteins. Despite substantial research on fibrillar collagen biosynthesis, our understanding of collagen IV biosynthesis, including its post-translational modifications (PTMs), remains limited. Most PTMs occur intracellularly, primarily within the endoplasmic reticulum (ER). In this review, we examine the molecular ensemble that orchestrates collagen IV biosynthesis in the ER, highlighting the complex interplay between prolyl and lysyl hydroxylases, glycosyltransferases, and molecular chaperones. Furthermore, we discuss how defects in collagen IV and its PTMs contribute to various human pathologies, including Gould and Alport syndromes, fibrosis, and cancer. Understanding collagen IV PTMs is crucial for elucidating the molecular basis of these diseases and improving targeted treatments. By reviewing our knowledge of collagen IV biosynthesis, we illustrate how this evolutionarily conserved yet highly specialized molecular biosynthesis ensemble supports the diverse functions of collagen IV in health and disease.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"140 ","pages":"Pages 59-77"},"PeriodicalIF":4.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Paracrine regulations of IFN-γ secreting CD4+ T cells by lumican and biglycan are protective in allergic contact dermatitis lumican和biglycan对IFN-γ分泌CD4+ T细胞的旁分泌调节在过敏性接触性皮炎中具有保护作用

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-06-14 DOI: 10.1016/j.matbio.2025.06.002

George Maiti , Jihane Frikeche , Cynthia Loomis , Michael Cammer , Stephanie L Eichman , Shukti Chakravarti

Allergic contact dermatitis (ACD) is a delayed-type IV hypersensitivity response driven by innate and adaptive immune cells. While specific immune regulations of these cell types are amply elucidated, their regulations by extracellular matrix (ECM) components and T cell mediated adaptive immunity in ACD remains unclear. Lumican and biglycan are ECM proteoglycans abundant in the dermis and lymph node, known to regulate innate immune myeloid cells, but have not been investigated in lymphoid cell regulations in ACD. By immunohistology we localized lumican and biglycan in skin biopsies of psoriatic patients. Using wild type (WT), lumican and biglycan knockout mice, we investigated CD4⁺T cell infiltration, activation and proliferation in the skin and draining lymph node (dLN) of contact hypersensitivity (CHS)-challenged mice by immunohistochemistry and flow cytometry. We used the OT-II adoptive transfer model to test antigen specific CD4⁺T cell activation. We assessed interactions of the proteoglycans with LFA-1 on T cells by confocal microscopy. Compared to WTs, the knockouts showed severe ear inflammation, with increased CD4⁺T cells infiltration in the dermis. CHS-challenged knockout mice dLN showed increased T-bet, STAT1 and -STAT4 signaling, indicating enhanced Th1 commitment and proliferation. We found that WT lymph node fibroblastic reticular cells (FRCs) secrete lumican, biglycan and decorin, a related proteoglycan, while none are expressed by naive or activated T cells. Lumican and biglycan interact with LFA-1 on T cell surfaces, and in vitro all three proteoglycans suppress CD4⁺T cell activation. Secreted by dLN FRCs, lumican, biglycan, and possibly decorin interact with LFA-1 on CD4⁺T cells to restrict their activation and reduce dermatitis severity.

过敏性接触性皮炎（ACD）是一种由先天和适应性免疫细胞驱动的延迟型IV超敏反应。虽然这些细胞类型的特异性免疫调节已被充分阐明，但它们在ACD中由细胞外基质（ECM）成分和T细胞介导的适应性免疫的调节尚不清楚。Lumican和biglycan是真皮和淋巴结中丰富的ECM蛋白聚糖，已知可调节先天性免疫髓细胞，但尚未研究ACD中淋巴样细胞的调节。通过免疫组织学方法，我们在银屑病患者的皮肤活检中定位了lumican和biglycan。以野生型（WT）、lumican和biglycan敲除小鼠为实验对象，采用免疫组织化学和流式细胞术研究了CD4+T细胞在chs小鼠皮肤和引流淋巴结（dLN）中的浸润、活化和增殖情况。我们使用OT-II过继转移模型来检测抗原特异性CD4+T细胞活化。我们通过共聚焦显微镜评估了蛋白聚糖与LFA-1在T细胞上的相互作用。与WTs相比，敲除组表现出严重的耳部炎症，真皮中CD4+T细胞浸润增加。chs敲除小鼠dLN显示T-bet、STAT1和-STAT4信号增加，表明Th1承诺和增殖增强。我们发现WT淋巴结成纤维网状细胞（FRCs）分泌lumican， biglycan和decorin，一种相关的蛋白聚糖，而未被初始或活化的T细胞表达。Lumican和biglycan在T细胞表面与LFA-1相互作用，并且这三种蛋白多糖在体外都能抑制CD4+T细胞的激活。由dLN FRCs分泌的lumican、biglycan和可能的decorin与CD4+T细胞上的LFA-1相互作用，限制其激活，降低皮炎的严重程度。

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引用次数: 0

A complex relationship between the architecture of the basement membrane, its mechanical properties, and its ability to shape the Drosophila egg 基膜的结构，它的机械特性，和它塑造果蝇卵的能力之间的复杂关系

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-06-13 DOI: 10.1016/j.matbio.2025.06.001

Mitchell T. Anderson , Sally Horne-Badovinac

Basement membranes (BMs) are planar extracellular matrices that line the basal surfaces of epithelia and are essential components of most organs. During development, BMs can also play instructive roles in shaping the tissues to which they belong, but how they do so is incompletely understood. The Drosophila egg chamber has become a premier system to study this aspect of BM biology due to the ostensible simplicity of the BM’s role in morphogenesis. The prevailing model posits that the egg chamber’s outer layer of epithelial cells creates a symmetric stiffness gradient in the surrounding BM that preferentially channels egg chamber growth along one axis to create the elongated shape of the egg. There is evidence that the stiffening of the BM depends, in part, on a polarized array of fibrils that form within the BM network, and yet the exact role the BM fibrils play in egg chamber elongation has remained unclear. Here, we use genetic conditions that abrogate fibril formation to different extents to probe the relationship between the BM’s fibril content, its mechanical properties, and the shape of the egg. The results of these experiments are consistent with a model in which BM fibrils influence egg shape by directly augmenting the mechanical properties of the BM. However, we then examine a final genetic condition that does not fit this simple narrative. We propose that the role of the BM in conferring final egg shape is more complicated than previously thought and that some approaches used to study this role should be re-evaluated for their efficacy.

基底膜是排列在上皮基底表面的平面细胞外基质，是大多数器官的重要组成部分。在发育过程中，脑转移瘤也可以在塑造它们所属的组织方面发挥指导作用，但它们是如何做到的还不完全清楚。由于果蝇卵室在形态发生中的作用表面上很简单，因此它已成为研究线粒体生物学这方面的首要系统。流行的模型假设，卵腔上皮细胞的外层在周围的BM中产生对称的刚度梯度，该梯度优先引导卵腔沿着一个轴生长，从而形成卵的细长形状。有证据表明，骨髓的硬化部分取决于骨髓网络中形成的原纤维的极化阵列，然而骨髓原纤维在卵室伸长中所起的确切作用仍不清楚。在这里，我们使用在不同程度上废除原纤维形成的遗传条件来探索BM的原纤维含量，其机械性能和卵的形状之间的关系。这些实验结果与BM原纤维通过直接增加BM的力学性能来影响卵形的模型一致。然而，我们接着检查一个最终的遗传条件，不符合这个简单的叙述。我们认为，卵细胞基质在决定最终卵子形状中的作用比以前认为的要复杂得多，一些用于研究这一作用的方法应该重新评估其有效性。

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引用次数: 0

Mechanical control of breast cancer malignancy by promotion of mevalonate pathway enzyme synthesis 促进甲羟戊酸途径酶合成对乳腺癌恶性肿瘤的机械控制

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-06-12 DOI: 10.1016/j.matbio.2025.05.005

Sara Göransson , Helene Olofsson , Henrik J. Johansson , Feifei Yan , Christos Vogiatzakis , Shuo Liang , Hermano Martins Bellato , Laia Masvidal , Inci Aksoylu , Johan Hartman , Glaucia NM Hajj , Ola Larsson , Janne Lehtiö , Staffan Strömblad

In breast cancer, mechanotransduction from stiffened extracellular matrix (ECM) drives proliferation and invasion. Here, we use a model of matrix stiffening mimicking progression of breast ductal carcinoma in situ to invasive ductal carcinoma. Quantitative mass spectrometry identified enrichment of ECM-stiffness upregulated mevalonate pathway enzymes, indicating sterol/isoprenoid metabolism reprogramming. Consistently, the first committed mevalonate pathway enzyme, Hydroxymethylglutaryl-CoA Synthase (HMGCS1), was upregulated in human breast cancer specimens and spatially correlated with cross-linked ECM. ECM-stiffness promoted HMGCS1 protein synthesis without corresponding mRNA level alterations, indicating post-transcriptional regulation of mevalonate biosynthesis via microenvironmental mechanical cues to impose rapid metabolic alterations. Moreover, HMGCS1-RNAi blocked the stiffness-driven breast cancer proliferative and invasive phenotype. Mechanistically, mechanotransduction signaling, through integrin and Rac1 to promote HMGCS1 protein expression, drives the breast cancer malignant phenotype. Intriguingly, the Rac1-P29S cancer mutant promoted a malignant phenotype without stiff ECM in a mevalonate-dependent manner. In summary, we define a mechano-responsive pathway controlling mevalonate pathway enzyme synthesis that drives breast cancer malignant behaviors.

在乳腺癌中，硬化细胞外基质（ECM）的机械转导驱动增殖和侵袭。在这里，我们使用基质硬化模型模拟乳腺导管原位癌向浸润性导管癌的进展。定量质谱鉴定出ecm僵硬度上调的甲戊酸途径酶的富集，表明甾醇/类异戊二烯代谢重编程。一致地，甲羟戊酸途径酶羟甲基戊二酰辅酶a合成酶（HMGCS1）在人类乳腺癌标本中上调，并与交联ECM在空间上相关。ecm刚度促进了HMGCS1蛋白的合成，但没有相应的mRNA水平改变，表明甲羟戊酸生物合成的转录后调控通过微环境机械线索施加快速代谢改变。HMGCS1-RNAi阻断了刚性驱动的乳腺癌增生性和侵袭性表型。机制上，机械转导信号通过整合素和Rac1促进HMGCS1蛋白表达，驱动乳腺癌恶性表型。有趣的是，Rac1-P29S癌症突变体以甲羟戊酸依赖的方式促进了没有僵硬ECM的恶性表型。总之，我们定义了一种机械反应途径，控制甲羟戊酸途径酶合成，驱动乳腺癌恶性行为。

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引用次数: 0

The functional role of the extracellular matrix in inflammatory bowel disease associated gut fibrosis 细胞外基质在炎症性肠病相关肠道纤维化中的功能作用

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-05-19 DOI: 10.1016/j.matbio.2025.05.001

Si-Nan Lin , Jie Wang , Pranab K. Mukherjee , Ido Veisman , William․ J․ Massey , Ren Mao , Jyotsna Chandra , Claudio Fiocchi , Florian Rieder

Intestinal fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) in the bowel wall. Complications, such as strictures that require surgical intervention in a large proportion of patients, are considered an inevitable consequence of chronic inflammation in inflammatory bowel disease (IBD) and leads to severe complications. The study of intestinal fibrosis in IBD has been traditionally focused on the associated immune process, and the role of the ECM itself has been largely overlooked. More recent studies have now clearly demonstrated that ECM is not simply a passive bystander of inflammation-driven fibrosis but is instead an active participant in the initiation and progression of the fibrogenic process. In this narrative review, we first describe the composition and function of the ECM components under physiological and pathological conditions of the gut. Then, we review the alterations of the intestinal ECM in IBD-associated fibrosis and the impact of fibrotic ECM on intestinal biology and function. We next critically evaluate the existing experimental systems to study the intestinal ECM, both in vitro and in vivo. We conclude by discussing the unique challenges that still exist to better understand the role of the ECM in intestinal fibrosis, and its potential diagnostic and therapeutic implications.

肠纤维化的特点是细胞外基质（ECM）在肠壁的过度积累。并发症，如大部分患者需要手术干预的狭窄，被认为是炎症性肠病（IBD）慢性炎症的不可避免的后果，并导致严重的并发症。传统上，IBD肠道纤维化的研究主要集中在相关的免疫过程上，而ECM本身的作用在很大程度上被忽视了。最近的研究已经清楚地表明，ECM不仅仅是炎症驱动纤维化的被动旁观者，而是纤维化过程的开始和进展的积极参与者。在这篇叙述性综述中，我们首先描述了肠道生理和病理条件下ECM成分的组成和功能。然后，我们回顾了肠ECM在ibd相关纤维化中的改变以及纤维化ECM对肠道生物学和功能的影响。接下来，我们在体外和体内对现有的实验系统进行批判性评估，以研究肠道ECM。最后，我们讨论了仍然存在的独特挑战，以更好地理解ECM在肠纤维化中的作用，及其潜在的诊断和治疗意义。

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引用次数: 0