Matrix Biology最新文献_第5页

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 : 2025-09-01 Epub 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

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 : 2025-09-01 Epub 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。

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引用次数: 0

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 : 2025-09-01 Epub 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

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 : 2025-09-01 Epub 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

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 : 2025-08-01 Epub 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

The life cycle of type IV collagen IV型胶原的生命周期

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-08-01 Epub Date: 2025-04-28 DOI: 10.1016/j.matbio.2025.04.004

Sandhya Srinivasan, David R. Sherwood

Type IV collagen is a large triple helical molecule that forms a covalently cross-linked network within basement membranes (BMs). Type IV collagen networks play key roles in mechanically supporting tissues, shaping organs, filtering blood, and cell signaling. To ensure tissue health and function, all aspects of the type IV collagen life cycle must be carried out accurately. However, the large triple helical structure and complex life-cycle of type IV collagen, poses many challenges to cells and tissues. Type IV collagen predominantly forms heterotrimers and to ensure proper construction, expression of the distinct α-chains that comprise a heterotrimer needs tight regulation. The α-chains must also be accurately modified by several enzymes, some of which are specific to collagens, to build and stabilize the triple helical trimer. In addition, type IV collagen is exceptionally long (400 nm) and thus the packaging and trafficking of the triple helical trimer from the ER to the Golgi must be modified to accommodate the large type IV collagen molecule. During ER-to-Golgi trafficking, as well as during secretion and transport in the extracellular space, type IV collagen also associates with specific chaperone molecules that maintain the structure and solubility of collagen IV. Type IV collagen trimers are then delivered to BMs from local and distant sources where they are integrated into BMs by interactions with cell surface receptors and many diverse BM resident proteins. Within BMs type IV collagen self-associates into a network and is crosslinked by BM resident enzymes. Finally, homeostatic type IV collagen levels in BMs are maintained by poorly understood mechanisms involving proteolysis and endocytosis. Here, we provide an overview of the life cycle of collagen IV, highlighting unique mechanisms and poorly understood aspects of type IV collagen regulation.

IV型胶原是一种大的三螺旋分子，在基底膜（BMs）内形成共价交联网络。IV型胶原蛋白网络在机械支持组织，塑造器官，过滤血液和细胞信号传导方面发挥关键作用。为了保证组织的健康和功能，IV型胶原蛋白生命周期的各个方面都必须准确地进行。然而，IV型胶原巨大的三螺旋结构和复杂的生命周期给细胞和组织带来了许多挑战。IV型胶原主要形成异源三聚体，为了确保正确的结构，组成异源三聚体的不同α-链的表达需要严格调节。α-链还必须被几种酶精确修饰，其中一些酶是胶原特异性的，以建立和稳定三螺旋三聚体。此外，IV型胶原蛋白非常长（400纳米），因此从内质网到高尔基体的三螺旋三聚体的包装和运输必须进行修改，以容纳大的IV型胶原蛋白分子。在内质网到高尔基体的运输过程中，以及在细胞外空间的分泌和运输过程中，IV型胶原还与维持IV型胶原结构和溶解度的特定伴侣分子结合。然后，IV型胶原三聚体通过与细胞表面受体和许多不同的BM驻留蛋白的相互作用，从局部和远处的来源被递送到脑转移瘤中。在脑基质内，IV型胶原自结合成一个网络，并由脑基质内的酶交联。最后，脑转移瘤中的稳态IV型胶原水平是通过蛋白质水解和内吞作用等机制维持的。在这里，我们概述了IV型胶原蛋白的生命周期，重点介绍了IV型胶原蛋白调节的独特机制和鲜为人知的方面。

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引用次数: 0

Interactions between cancer-associated fibroblasts and the extracellular matrix in oesophageal cancer 食管癌中癌相关成纤维细胞与细胞外基质的相互作用。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-08-01 Epub Date: 2025-05-14 DOI: 10.1016/j.matbio.2025.05.003

Subashan Vadibeler , Shannique Clarke , Su M. Phyu , Eileen E. Parkes

Stromal components of the tumour microenvironment, such as cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM), are actively involved in tumorigenesis. CAFs and the ECM co-evolve with resultant molecular and mechanical pressure on tumour cells mediated by CAFs via the ECM. Meanwhile, ECM fibers determine CAF differentiation and activity, establishing a protumorigenic feed-forward loop. Oesophageal cancer carries a high morbidity and mortality, and curative surgical resection is only an option for a limited number of patients while early lymphatic spread and poor therapeutic responses are common. Although studies report marked heterogeneity in investigation of the stromal density of gastrointestinal cancers, it is generally accepted that oesophageal cancer is highly fibrotic, and stromal components like CAFs may outnumber cancer cells. Therefore, a comprehensive understanding of the reciprocal interaction between CAFs and the ECM in oesophageal cancer is essential to improving diagnostics and prognostication, as well as designing innovative anti-cancer strategies. Here, we summarise current understanding of oesophageal cancer from a stromal perspective. Then, we discuss that CAFs and the ECM in oesophageal cancer can independently and synergistically contribute to tumour progression and therapeutic resistance. We also summarise potential stromal targets that have been described in transcriptomic analyses, highlighting those validated in downstream experimental studies. Importantly, clinical translation of stromal-targeting strategies in oesophageal cancer is still in its infancy but holds significant promise for future therapeutic combinations.

肿瘤微环境的基质成分，如癌症相关成纤维细胞（CAFs）和细胞外基质（ECM），积极参与肿瘤的发生。CAFs和ECM共同进化，由CAFs通过ECM介导对肿瘤细胞产生分子和机械压力。同时，ECM纤维决定CAF的分化和活性，建立了一个致蛋白前馈回路。食管癌具有很高的发病率和死亡率，治疗性手术切除仅是少数患者的一种选择，而早期淋巴扩散和治疗反应差是常见的。虽然研究报告了胃肠道肿瘤间质密度的异质性，但人们普遍认为食管癌是高度纤维化的，cas等间质成分的数量可能超过癌细胞。因此，全面了解食管癌中caf和ECM之间的相互作用对于提高诊断和预后以及设计创新的抗癌策略至关重要。在这里，我们从基质的角度总结了目前对食管癌的认识。然后，我们讨论了食管癌中的caf和ECM可以独立地和协同地促进肿瘤进展和治疗耐药性。我们还总结了转录组学分析中描述的潜在基质靶点，强调了那些在下游实验研究中得到验证的靶点。重要的是，食管癌基质靶向策略的临床转化仍处于起步阶段，但对未来的治疗组合具有重要的前景。

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引用次数: 0

Differential modulation of endothelial cell functionality by LRP1 expression in fibroblasts and cancer-associated fibroblasts via paracrine signals and matrix remodeling 通过旁分泌信号和基质重塑，LRP1在成纤维细胞和癌症相关成纤维细胞中的表达对内皮细胞功能的差异调节。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-08-01 Epub Date: 2025-05-14 DOI: 10.1016/j.matbio.2025.05.004

Julie Martin , Auréana Falaise , Sara Faour , Christine Terryn , Cathy Hachet , Émilie Thiébault , Louise Huber , Pierre Nizet , Damien Rioult , Rodolphe Jaffiol , Stéphanie Salesse , Stéphane Dedieu , Benoit Langlois

LRP1 is a multifunctional endocytosis receptor involved in the regulation of cancer cell aggressiveness, fibroblast phenotype and angiogenesis. In breast cancer microenvironment, cancer-associated fibroblasts (CAFs) play a crucial role in matrix remodeling and tumor niche composition. LRP1 expression was described in fibroblasts and CAFs but remains poorly understood regarding its impact on endothelial cell behavior and angiocrine signaling. We analyzed the angio-modulatory effect of LRP1 expression in murine embryonic fibroblasts (MEFs) and breast cancer-educated CAF₂ cells. We employed conditioned media and fibroblast-derived matrices to model fibroblastic cells angiogenic effects on human umbilical vein endothelial cells (HUVEC). Neither the extracellular matrix assembled by MEFs knock-out for LRP1 (PEA-13) nor their secretome modify the migration of HUVEC as compared to wild-type. Conversely, LRP1-deficient CAF₂ secretome and matrices stimulate endothelial cell migration. Using spheroids, we demonstrate that PEA-13 secretome does not affect HUVEC angio-invasion. By contrast, CAF₂ secretome invalidated for LRP1 stimulates endothelial sprouting as compared to controls. In addition, it specifically stabilized peripheral VE-cadherin-mediated endothelial cell junctions. A global proteomic analysis revealed that LRP1 expression in CAFs orchestrates a specific mobilization of secreted matricial components, surface receptors and membrane-associated proteins at the endothelial cell surface, thereby illustrating the deep influence exerted by LRP1 in angiogenic signals emitted by activated fibroblasts.

LRP1是一种多功能内吞受体，参与癌细胞侵袭性、成纤维细胞表型和血管生成的调节。在乳腺癌微环境中，癌症相关成纤维细胞（CAFs）在基质重塑和肿瘤生态位组成中起着至关重要的作用。LRP1在成纤维细胞和CAFs中表达，但对其对内皮细胞行为和血管分泌信号的影响仍知之甚少。我们分析了LRP1表达在小鼠胚胎成纤维细胞（mef）和乳腺癌诱导的CAF2细胞中的血管调节作用。我们使用条件培养基和成纤维细胞衍生基质来模拟成纤维细胞对人脐静脉内皮细胞（HUVEC）的血管生成作用。与野生型相比，mef敲除LRP1 （PEA-13）组装的细胞外基质及其分泌组都不能改变HUVEC的迁移。相反，缺乏lrp1的CAF2分泌组和基质会刺激内皮细胞迁移。使用球体，我们证明PEA-13分泌组不影响HUVEC血管侵袭。相比之下，与对照组相比，LRP1无效的CAF2分泌组刺激内皮细胞发芽。此外，它还能特异性稳定外周ve -钙粘蛋白介导的内皮细胞连接。一项全球蛋白质组学分析显示，LRP1在cas中的表达协调了内皮细胞表面分泌的物质成分、表面受体和膜相关蛋白的特异性动员，从而说明了LRP1对活化成纤维细胞发出的血管生成信号的深刻影响。

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引用次数: 0

Load activated FGFR and beta1 integrins target distinct chondrocyte mechano-response genes 负载激活的FGFR和β 1整合素靶向不同的软骨细胞机械反应基因。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-08-01 Epub Date: 2025-05-14 DOI: 10.1016/j.matbio.2025.05.002

Helen F. Dietmar , Pia A. Weidmann , Paolo Alberton , Terrilyn Teichwart , Matthias Gerstner , Tobias Renkawitz , Andrea Vortkamp , Attila Aszodi , Wiltrud Richter , Solvig Diederichs

In response to mechanical stimuli, chondrocytes adapt their transcriptional activity, thereby shaping the cellular mechano-response; however, it remains unclear whether the activation of cell surface receptors during mechanical loading converge in the activation of the same mechano-response genes, or whether pathway-specific genes can be defined. We aimed to determine whether load-activated FGF/FGFR signalling and β1 integrins activate ERK and control the same or distinct subsets of mechano-regulated genes. To this end, tissue-engineered neocartilage was generated from murine costal chondrocytes or human articular chondrocytes and subjected to dynamic unconfined compression with or without FGFR inhibition. To assess the role of β1 integrins, neocartilage was generated from embryonic β1 integrin-deficient or wild type costal chondrocytes.

Load-activated FGFR signalling drove ERK activation in murine chondrocytes, and partially also in human chondrocytes, and mechano-response genes could be classified according to their regulation: Fosl1, Itga5, Ngf and Timp1 were regulated by load-activated FGFR depending on the developmental stage, whereas β1 integrins controlled Inhba expression. In human chondrocytes, load-activated FGFR signalling controlled expression of BMP2, PTGS2 and DUSP5, but not FOSB.

We show here that the chondrocyte loading response is coordinated by concurrent activation of multiple receptors, and identified for the first time distinct target genes of activated receptors. These insights open up the opportunity to pharmacologically shape the mechano-response of chondrocytes in future studies with promising implications for the management of osteoarthritis and the development of novel therapeutic strategies.

为了响应机械刺激，软骨细胞调整其转录活性，从而形成细胞机械反应；然而，目前尚不清楚在机械负荷过程中细胞表面受体的激活是否聚集在相同的机械反应基因的激活中，或者是否可以定义途径特异性基因。我们的目的是确定负载激活的FGF/FGFR信号传导和β1整合素是否激活ERK并控制相同或不同的机械调节基因亚群。为此，组织工程的新软骨由小鼠肋软骨细胞或人关节软骨细胞生成，并在有或没有FGFR抑制的情况下进行动态无侧限压缩。为了评估β1整合素的作用，我们从胚胎β1整合素缺失或野生型肋软骨细胞中生成新软骨。负载激活的FGFR信号传导在小鼠软骨细胞中驱动ERK激活，部分也在人软骨细胞中，机械反应基因可以根据其调节进行分类：负载激活的FGFR根据发育阶段调节Fosl1， Itga5， Ngf和Timp1，而β1整合素控制Inhba的表达。在人软骨细胞中，负荷激活的FGFR信号传导控制BMP2、PTGS2和DUSP5的表达，但不控制FOSB。我们在这里表明，软骨细胞负荷反应是通过多个受体的同时激活来协调的，并首次确定了激活受体的不同靶基因。这些见解为在未来的研究中从药理学上塑造软骨细胞的机械反应提供了机会，对骨关节炎的治疗和新治疗策略的发展具有重要意义。

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引用次数: 0

Brain vascular basement membrane: Comparison of human and mouse brain at the transcriptomic and proteomic levels 脑血管基底膜：人类和小鼠大脑转录组学和蛋白质组学水平的比较

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-08-01 Epub Date: 2025-04-26 DOI: 10.1016/j.matbio.2025.04.003

Nan Zhao , Alexander F. Pessell , Tracy D. Chung , Peter C. Searson

The cerebrovascular basement membrane (BM) is a key component of the blood-brain barrier (BBB). The BM provides structural support for brain microvascular endothelial cells and the supporting cells of the neurovascular unit, and facilitates cell signaling through adhesion receptors, regulates the concentration of soluble factors, and serves as an additional barrier for transport. However, our understanding of the composition of BM remains incomplete. Here we analyze recent proteomic and genomic data to assess the composition of BM in human and mouse brain, and in tissue-engineered BBB models. All data sets confirm that the main components of brain BM are collagen IV a1/2 and laminin, along with agrin, perlecan, and nidogen. Transcriptomic data from human BMECs suggests that the main laminin isoform is Laminin 321, while transcriptomic data from mice and proteomic data from mice and humans suggest that Laminin 521 is the predominant isoform. Transcriptomic data from iBMECs suggest that Laminin 511 is the predominant isoform. The supporting molecules agrin, perlecan, and nidogen were detected at significant levels in all studies, although only nidogen 1 was detected in the human transcriptomic data sets. No significant differences in human BM composition were observed in BMECs along the arterio-venous axis, or in comparison of healthy and AD brains.

脑血管基底膜（BM）是血脑屏障（BBB）的重要组成部分。脑基质为脑微血管内皮细胞和神经血管单元的支持细胞提供结构支持，并通过粘附受体促进细胞信号传导，调节可溶性因子的浓度，并作为运输的额外屏障。然而，我们对BM的组成的了解仍然不完整。在这里，我们分析了最近的蛋白质组学和基因组学数据，以评估人脑和小鼠大脑以及组织工程血脑屏障模型中脑基质的组成。所有数据集均证实脑基底膜的主要成分是胶原IV a1/2和层粘连蛋白，以及蛋白、蛋白聚糖和氮原。来自人bmec的转录组学数据表明，层粘连蛋白的主要亚型是层粘连蛋白321，而来自小鼠的转录组学数据和来自小鼠和人类的蛋白质组学数据表明，层粘连蛋白521是主要亚型。来自ibmec的转录组学数据表明层粘连蛋白511是主要的亚型。支持分子agin， perlecan和nidogen在所有研究中都被检测到显著水平，尽管只有nidogen 1在人类转录组数据集中被检测到。在沿动-静脉轴的bmec中，或在健康和AD脑的比较中，未观察到人类脑基质成分的显著差异。

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