Matrix Biology最新文献_第6页

Oligomerisation of pentraxin-3: Insights from cryoEM 五胜肽-3的寡聚化：低温电子显微镜的启示。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-04-03 DOI: 10.1016/j.matbio.2025.04.001

Antonio Inforzato , Anthony J. Day

Pentraxin-3 (PTX3) is a secreted protein with roles in the stabilisation of hyaluronan-rich extracellular matrices involved in reproductive biology and inflammatory processes, as well as additional functions in innate immunity and cancer. Our recent structural studies (Shah et al., 2025; DOI:10.1016/j.matbio.2025.01.002), involving X-ray crystallography, cryo-electron microscopy (cryoEM) and AlphaFold modelling, have provided clues as to how PTX3 becomes assembled into an octamer from eight identical protomer subunits. Here it was proposed that four protomers initially form a tetramer, composed of a highly extended N-terminal region consisting of coiled-coil structures and C-terminal pentraxin domains, where two tetramers then immediately align and associate via an extensive network of salt bridges, allowing stabilisation of the octamer via the formation of disulphide bonds. However, a paper published around the same time provides an alternative perspective (Guo et al., 2025; DOI: 10.1016/j.ijbiomac.2024.139207). The authors propose, based on cryoEM analyses, that in addition to octamers, stable dimers, tetramers and hexamers of PTX3 can also assemble, where it is the dimers that provide the ‘building blocks’ for generation of the various oligomeric forms. In this commentary we suggest that the presence of dimers, tetramers and hexamers is likely an artefact of the construct used in recombinant expression, since the existence of these oligomers is not consistent with other studies on PTX3. We also provide a model to clarify how protomers become assembled into an octamer via sequential formation of a disulphide-linked tetramer, non-covalent association of two tetramers through aligned ionic interactions and the formation of disulphide bonds between the C-terminal pentraxin domains.

penttraxin -3 （PTX3）是一种分泌蛋白，在稳定富含透明质酸的细胞外基质中发挥作用，参与生殖生物学和炎症过程，以及在先天免疫和癌症中发挥额外功能。我们最近的结构研究(Shah et al., 2025；DOI:10.1016/j.matbio.2025.01.002)，涉及x射线晶体学，低温电子显微镜（cryoEM）和AlphaFold建模，提供了关于PTX3如何从八个相同的原聚体亚基组装成八聚体的线索。本文提出，四个原聚体最初形成一个四聚体，由一个高度延伸的n端区域组成，该区域由卷曲的线圈结构和c端戊烷素结构域组成，其中两个四聚体随后通过广泛的盐桥网络立即对齐并结合，从而通过形成二硫键来稳定八聚体。然而，大约在同一时间发表的一篇论文提供了另一种观点(Guo et al., 2025；DOI: 10.1016 / j.ijbiomac.2024.139207)。基于低温电镜分析，作者提出，除了八聚体外，PTX3的稳定二聚体、四聚体和六聚体也可以组装，其中二聚体为生成各种低聚体形式提供了“构建块”。在这篇评论中，我们认为二聚体、四聚体和六聚体的存在可能是重组表达中使用的结构的人工产物，因为这些低聚物的存在与其他关于PTX3的研究不一致。我们还提供了一个模型来阐明原聚体是如何通过二硫化物连接的四聚体的顺序形成、两个四聚体通过排列的离子相互作用的非共价结合以及在c端戊烷素结构域之间形成二硫化物键而组装成八聚体的。

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引用次数: 0

Toward a rational therapeutic for elastin related disease: Key considerations for elastin based regenerative medicine strategies 迈向弹性蛋白相关疾病的合理治疗：基于弹性蛋白的再生医学策略的关键考虑。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-03-28 DOI: 10.1016/j.matbio.2025.03.003

Meysam Ganjibakhsh , Yanina Tkachenko , Russell H. Knutsen , Beth A. Kozel

Elastin is a connective tissue protein, produced from the ELN gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window. Consequently, elastin-related disease comes about primarily in one of three scenarios: (1) inadequate elastin deposition, (2) production of poor-quality elastic fibers, or (3) increased destruction of previously deposited elastin. By understanding the pathways controlling elastin production and maintenance, we can design new therapeutics to thwart those abnormal processes. In this review, we will summarize the diseases arising from genetic and environmental alteration of elastin (Williams syndrome, supravalvar aortic stenosis, autosomal dominant cutis laxa, and ELN-related vascular and connective tissue dysfunction) and then describe the mechanisms controlling elastin production and maintenance that might be manipulated to generate novel therapeutics aimed at these conditions. We will end by summarizing existing therapeutic strategies targeting these disease mechanisms before outlining future approaches that may better solve the challenges associated with elastin based regenerative medicine.

弹性蛋白是一种结缔组织蛋白，由 ELN 基因产生，可为人体大动脉、肺实质、皮肤、韧带和弹性软骨等伸展组织提供弹性和反冲力。它以可溶性单体特罗波弹性蛋白（tropoelastin）的形式产生，在细胞外空间交联后生成的聚合物异常稳定，半衰期预计超过 70 年。尽管有数据表明弹性蛋白的转录仍在进行，但很少能看到新的弹性蛋白在其紧密的发育窗口外沉积。因此，与弹性蛋白相关的疾病主要有三种情况：1）弹性蛋白沉积不足；2）产生劣质弹性纤维；或3）先前沉积的弹性蛋白破坏加剧。通过了解控制弹性蛋白生成和维持的途径，我们可以设计出新的疗法来阻止这些异常过程。在这篇综述中，我们将总结因弹性蛋白的遗传和环境改变而导致的疾病（威廉姆斯综合征、主动脉瓣上狭窄、常染色体显性遗传性皮肤松弛症以及与ELN相关的血管和结缔组织功能障碍），然后描述控制弹性蛋白生成和维持的机制，这些机制可能会被用于产生针对这些疾病的新型疗法。最后，我们将总结针对这些疾病机制的现有治疗策略，然后概述未来可能更好地解决弹性蛋白再生医学相关挑战的方法。

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引用次数: 0

Structural insights on perlecan and Schwartz–Jampel syndrome 关于perlecan和Schwartz-Jampel综合征的结构见解。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-03-19 DOI: 10.1016/j.matbio.2025.03.002

Anil A. Sohail , M. Kristian Koski , Lloyd W. Ruddock

Perlecan is an essential multi-domain, disulfide bond rich basement membrane protein. Mutations in perlecan cause Schwartz-Jampel syndrome and dyssegmental dysplasia. While there has been a large body of experimental work reported on perlecan, there is only minimal structural information available to date. There is no prior structural data for region 3 of perlecan in which some Schwartz-Jampel syndrome causing point mutations have been reported. Here, we produce constructs of the disulfide rich region 3 of perlecan along with five mutations previously reported to cause Schwatz-Jampel syndrome. Four of the mutations resulted in decreased yields and thermal stability compared to the wild-type protein. In contrast, the P1019L mutation was produced in good yields and showed higher thermal stability than the wild-type protein. The crystal structures for both the wild-type and P1019L mutation were solved. As expected, both showed laminin IV-like and laminin-type EGF-like domains, with the P1019L mutation resulting in only a minor conformational change in a loop region and no significant changes in regular secondary or tertiary structure.

Perlecan是一种重要的多结构域、富含二硫键的基底膜蛋白。perlecan突变导致Schwartz-Jampel综合征和节段性发育不良。虽然已经有大量关于perlecan的实验工作报告，但迄今为止只有最少的结构信息可用。perlecan的3区没有先前的结构数据，其中一些Schwartz-Jampel综合征引起的点突变已被报道。在这里，我们构建了perlecan的富二硫区3以及先前报道的导致Schwatz-Jampel综合征的五种突变。与野生型蛋白相比，其中四个突变导致产量和热稳定性下降。相比之下，P1019L突变蛋白产量较高，热稳定性优于野生型蛋白。对野生型和P1019L突变的晶体结构进行了分析。正如预期的那样，两者都表现出层粘连蛋白iv样和层粘连蛋白型egf样结构域，P1019L突变仅导致环区轻微的构象变化，规则的二级或三级结构没有明显变化。

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引用次数: 0

Circulating collagen type I fragments as specific biomarkers of cardiovascular outcome risk: Where are the opportunities? 循环I型胶原片段作为心血管结局风险的特定生物标志物：机会在哪里？

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-03-02 DOI: 10.1016/j.matbio.2025.03.001

Emily M. Martin , Joan Chang , Arantxa González , Federica Genovese

Collagen type I (COL1) is the most abundant protein in the human body and is a main component in the extracellular matrix. The COL1 structure vastly influences normal tissue homeostasis, and changes in the matrix drive progression in multiple diseases. Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in many Western countries; alterations in the extracellular matrix turnover processes, including COL1, are known to influence the pathophysiological processes leading to CVD outcome. Peptides reflecting COL1 formation and degradation have been established and explored for over two decades in CVD. This review aims to combine and assess the evidence for using COL1-derived circulating peptides as biomarkers in CVD. Secondly, the review identifies existing pitfalls, and evaluates future opportunities for improving the technical characteristics and performance of the biomarkers for implementation in the clinical setting.

I型胶原蛋白（COL1）是人体内最丰富的蛋白质，是细胞外基质的主要成分。COL1结构极大地影响正常组织的稳态和基质的变化驱动多种疾病的进展。心血管疾病（CVD）是许多西方国家死亡率和发病率的主要原因；包括COL1在内的细胞外基质转换过程的改变，已知会影响导致心血管疾病结果的病理生理过程。反映COL1形成和降解的肽已经在CVD中建立和探索了二十多年。本综述旨在结合和评估使用col1衍生循环肽作为CVD生物标志物的证据。其次，该综述确定了现有的缺陷，并评估了未来的机会，以改善生物标志物的技术特征和性能，以便在临床环境中实施。

引用次数: 0

Laminins and the blood-brain barrier 层粘连蛋白和血脑屏障。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-03-01 DOI: 10.1016/j.matbio.2025.02.005

Ava Nasrollahi, Yao Yao

The blood-brain barrier (BBB) is a dynamic structure that maintains brain homeostasis. BBB breakdown is a key pathological hallmark of almost all neurological diseases. Although the regulation of BBB integrity by different cells has been extensively studied, the function of its non-cellular component—the basal lamina in BBB regulation remains largely unknown. Laminin, a trimeric protein with multiple isoforms, is one of the most important constituents of the basal lamina. In the CNS, different cells synthesize distinct laminin isoforms, which differentially regulate BBB integrity in both physiological and pathological conditions. A thorough understanding of laminin expression and function in BBB integrity could lead to the identification of novel therapeutic targets and potentially result in effective treatments for neurological disorders involving BBB disruption. Here in this review, we first briefly introduce the BBB and basal lamina with a focus on laminin. Next, we elucidate laminin expression and its function in BBB maintenance/repair in a cell-specific manner. Potential functional compensation among laminin isoforms is also discussed. Last, current challenges in the field and future directions are summarized. Our goal is to provide a synthetic review to encourage novel ideas and stimulate new research in the field.

血脑屏障（BBB）是维持大脑稳态的动态结构。血脑屏障破坏是几乎所有神经系统疾病的关键病理标志。尽管不同细胞对血脑屏障完整性的调节已被广泛研究，但其非细胞成分-基底膜在血脑屏障调节中的作用仍不甚清楚。层粘连蛋白是一种具有多种异构体的三聚体蛋白，是基底层最重要的成分之一。在中枢神经系统中，不同的细胞合成不同的层粘连蛋白异构体，在生理和病理条件下对血脑屏障的完整性进行不同的调节。深入了解层粘连蛋白在血脑屏障完整性中的表达和功能，可能会导致新的治疗靶点的确定，并可能导致涉及血脑屏障破坏的神经系统疾病的有效治疗。在这篇综述中，我们首先简要介绍血脑屏障和基板，重点介绍层粘连蛋白。接下来，我们以细胞特异性的方式阐明层粘连蛋白的表达及其在血脑屏障维持/修复中的功能。层粘连蛋白异构体之间潜在的功能补偿也进行了讨论。最后，总结了该领域当前面临的挑战和未来的发展方向。我们的目标是提供一个综合的评论，以鼓励新颖的想法和刺激新的研究领域。

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引用次数: 0

Mysteries of the collagen triple helix 胶原蛋白三螺旋的奥秘。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-02-14 DOI: 10.1016/j.matbio.2025.02.003

Hans Peter Bächinger , Sergei P. Boudko

The collagen triple helix is one of the structurally simplest protein motifs that still holds a lot of secrets. The Gly-X-Y repeat is a business card of collagens, where Gly is required for the tight packing of three helices into a superhelix and X and Y residues are important for stabilizing the triple helix and communicating with the world. On its way to a functional molecule, collagen sequences undergo unique post-translational modifications inside and outside of the cell. Moreover, folding and secretion of collagens require specific proteins and mechanisms. Cracking the collagen triple helix codes opens up opportunities for curing associated diseases and developing new biomaterials. Here, we summarized my journey through some mysteries of the collagen triple helix and point out key unaddressed questions and problems for other researchers to pursue.

胶原蛋白三螺旋结构是结构最简单的蛋白质基序之一，它仍然拥有许多秘密。Gly-X-Y重复序列是胶原的名片，其中Gly是将三个螺旋紧密包装成超螺旋所必需的，而X和Y残基对于稳定三螺旋和与外界沟通很重要（图1）。在成为功能分子的过程中，胶原序列在细胞内外经历了独特的翻译后修饰。此外，胶原蛋白的折叠和分泌需要特定的蛋白质和机制。破解胶原蛋白三螺旋密码为治疗相关疾病和开发新的生物材料开辟了机会。在这里，我们总结了我对胶原蛋白三螺旋结构的一些神秘之旅，并指出了其他研究人员需要解决的关键问题和问题。

引用次数: 0

Inhibition of the MRTF-A/SRF signaling axis alleviates vocal fold scarring 抑制MRTF-A/SRF信号轴可减轻声带瘢痕形成。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-02-14 DOI: 10.1016/j.matbio.2025.02.004

Ryan M. Friedman , Huy D. Truong , Matthew R. Aronson , Elizabeth A. Brown , Marco Angelozzi , Jeffrey F. Chen , Karen B. Zur , Véronique Lefebvre , Riccardo Gottardi

Vocal fold scarring, the most common cause of poor voice after airway injury, involves the transition of vocal fold fibroblasts to contractile myofibroblasts. Vocal fold myofibroblasts can be characterized by significant extracellular matrix (ECM) secretion and stress fiber formation. Biochemical signals, such as transforming growth factor (TGF)-β1, and biophysical cues, such as matrix stiffening, have been shown to induce the fibroblast-to-myofibroblast transition. To identify key intracellular pathways that may mediate myofibroblast activation, we performed bulk RNA sequencing of human vocal fold fibroblasts treated with or without TGF-β1 and found that genes downstream of myocardin related transcription factor A (MRTF-A) and serum response factor (SRF) were upregulated in TGFβ1-induced myofibroblasts. We then show that both TGF-β1 and ECM stiffening induce MRTF-A and SRF nuclear translocation during vocal fold myofibroblast activation. Inhibition of MRTF-A via CCG-257,081 reduced pro-fibrotic gene expression, the percentage of α-smooth muscle actin (α-SMA)-positive fibroblasts, and cell contractility in vitro. In a murine model of vocal fold scarring, MRTF-A inhibition reduced vocal fold scarring severity, evidenced by reduced epithelial thickening, decreased glycosaminoglycan content, and collagen deposition, and decreased expression of ACTA2. Our study suggests that the MRTF-A/SRF pathway regulates vocal fold myofibroblast activation, and that inhibition of MRTF-A has a protective effect against vocal fold scarring in mice.

声带瘢痕形成是气道损伤后声音不佳的最常见原因，涉及声带成纤维细胞向收缩性肌成纤维细胞的转变。声带肌成纤维细胞的特征是细胞外基质（ECM）分泌和应激纤维的形成。生物化学信号，如转化生长因子(TGF)-β1，和生物物理信号，如基质硬化，已被证明可以诱导成纤维细胞向肌成纤维细胞转变。为了确定可能介导肌成纤维细胞活化的关键细胞内通路，我们对TGF-β1或不TGF-β1处理的人声带成纤维细胞进行了大量RNA测序，发现在TGF-β1诱导的肌成纤维细胞中，心肌素相关转录因子A （MRTF-A）和血清反应因子（SRF）下游基因上调。然后我们发现TGF-β1和ECM硬化在声带肌成纤维细胞激活过程中诱导MRTF-A和SRF核易位。CCG-257081抑制MRTF-A可降低促纤维化基因表达、α-平滑肌肌动蛋白（α-SMA）阳性成纤维细胞百分比和细胞体外收缩性。在小鼠声带瘢痕模型中，MRTF-A抑制降低了声带瘢痕的严重程度，表现为上皮增厚减少，糖胺聚糖含量减少，胶原沉积减少，ACTA2表达降低。我们的研究表明，MRTF-A/SRF通路调节声带肌成纤维细胞的激活，抑制MRTF-A对小鼠声带瘢痕形成具有保护作用。

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引用次数: 0

Role of syndecan-4 in angiogenesis and vasculogenic mimicry in triple negative breast cancer cells syndecan-4在三阴性乳腺癌细胞血管生成和血管生成模拟中的作用。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-02-10 DOI: 10.1016/j.matbio.2025.02.002

Jessica Oyie Sousa Onyeisi , Heba M. El-Shorafa , Burkhard Greve , Martin Götte

Syndecan-4 (SDC4), a heparan sulfate proteoglycan, is aberrantly expressed in breast cancer and plays a significant role in tumor progression by influencing cell proliferation and promoting invasive growth. This study aimed to characterize its role in the tumor microenvironment by analyzing the contribution of SDC4 to vasculogenic mimicry (VM) and angiogenesis in human breast cancer cells. We silenced SDC4 in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231, MDA-MB-468, and SUM-149 and analyzed its functions in vitro. SDC4 knockdown inhibited the VM of MDA-MB-231 cells as analyzed by fluorescence microscopy. Moreover, RT-qPCR revealed decreased expression of KLF4, EGR1, and HPSE, factors involved in VM, proangiogenic and pro-invasive processes in all TNBC cell lines. Western blotting revealed a partially cell-line-dependent regulation of these proteins by SDC4. At the functional level, SDC4 knockdown also impaired angiogenesis, decreasing the number of nodes and meshes in a 3D co-culture model comprising endothelial cells and TNBC cells. Using a Proteome Profile Human Angiogenesis Array, we observed that SDC4 knockdown decreased the secretion of VEGF and IGFBP-1, while it increased the secretion of IL-8, uPA, and amphiregulin in the conditioned media of the MDA-MB-231 and MDA-MB-468 co-cultures. Independent RT-qPCR analyses of gene expression were consistent with those of the angiogenesis array. Overall, these findings highlighted the crucial role of SDC4 in regulating both vasculogenic mimicry and angiogenesis in TNBC cells. The data indicate that SDC4 acts as a crucial regulatory molecule and represents a promising target for therapeutic strategies in breast cancer.

Syndecan-4 （SDC4）是一种硫酸肝素蛋白多糖，在乳腺癌中异常表达，并通过影响细胞增殖和促进侵袭性生长在肿瘤进展中发挥重要作用。本研究旨在通过分析SDC4对人乳腺癌细胞血管生成模拟（VM）和血管生成的贡献来表征其在肿瘤微环境中的作用。我们在三阴性乳腺癌（TNBC）细胞株MDA-MB-231、MDA-MB-468和SUM-149中沉默SDC4，并在体外分析其功能。荧光显微镜观察发现，SDC4基因敲低对MDA-MB-231细胞的VM有抑制作用。此外，RT-qPCR结果显示，在所有TNBC细胞系中，参与VM、促血管生成和促侵袭过程的因子KLF4、EGR1和HPSE的表达均下降。Western blotting显示SDC4部分依赖细胞系调节这些蛋白。在功能水平上，SDC4敲低也会损害血管生成，减少内皮细胞和TNBC细胞组成的3D共培养模型中的节点和网格数量。在MDA-MBA-231和MDA-MB-468共培养的条件培养基中，我们观察到SDC4敲低降低了VEGF和IGFBP-1的分泌，而增加了IL-8、uPA和双调节蛋白的分泌。基因表达的独立RT-qPCR分析与血管生成阵列的结果一致。总之，这些发现强调了SDC4在调节TNBC细胞血管生成模拟和血管生成中的关键作用。这些数据表明，SDC4作为一个关键的调控分子，代表了乳腺癌治疗策略的一个有希望的靶点。

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引用次数: 0

Dystrophic epidermolysis bullosa - From biochemistry to interventions 萎缩性表皮松解症--从生物化学到干预措施

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-02-06 DOI: 10.1016/j.matbio.2025.02.001

Alexander Nyström

The skin, as a barrier organ meeting constant mechanical challenges, is equipped with multiple adhesive structures that collectively support resilient, yet flexible attachment of its epithelium –the epidermis to its mesenchyme – the dermis. One such structure is the collagen VII-composed anchoring fibril, which provides firm anchorage of the epidermal basement membrane to the underlying interstitial extracellular matrix. Blistering and wider tissue fragility in the genetic disease dystrophic epidermolysis bullosa (DEB) caused by collagen VII deficiency illustrate the essential function of collagen VII in supporting skin integrity. DEB is also a progressive inflammatory fibrotic disease with multi-organ involvement, indicating that collagen VII has broader functions than simply providing epithelial anchorage. This review explores the reciprocal relationship between collagen VII biology and DEB pathophysiology. A deeper understanding of collagen VII biology – spanning its synthesis, assembly into suprastructures, and regulatory roles – enhances our understanding of DEB. Conversely, detailed insights into DEB through analysis of disease progression or therapeutic interventions offer valuable information on the broader tissue and organismal roles of collagen VII in maintaining homeostasis. This review focuses on such knowledge exchange in advancing our understanding of collagen VII, the extracellular matrix in general, and inspiring potential strategies for treatment of DEB. Importantly, in a broader sense, the discussed themes are applicable to other conditions driven by compromised extracellular matrix instruction and integrity, leading to progressive damage and inflammation.

皮肤作为一种屏障器官，具有多种粘附结构，这些结构共同支持其上皮（表皮）与间质（真皮层）的弹性和柔性附着。其中一种结构是由vii型胶原组成的锚定纤维，它为表皮基底膜提供牢固的锚定，使其与下层间质细胞外基质相连。由VII型胶原缺乏引起的遗传性疾病大疱性营养不良性表皮松解症（DEB）的起泡和更广泛的组织脆性说明了VII型胶原在支持皮肤完整性方面的重要功能。DEB也是一种累及多器官的进行性炎性纤维化疾病，这表明VII型胶原具有比单纯提供上皮锚定更广泛的功能。本文就VII型胶原蛋白生物学与DEB病理生理学之间的相互关系作一综述。对VII型胶原蛋白生物学的深入了解-跨越其合成，组装到上层结构和调节作用-增强了我们对DEB的理解。相反，通过对疾病进展或治疗干预的分析，对DEB的详细了解为VII胶原在维持体内平衡方面更广泛的组织和机体作用提供了有价值的信息。这篇综述的重点是这种知识交流，以促进我们对胶原VII的理解，一般的细胞外基质，并启发潜在的治疗DEB的策略。重要的是，从更广泛的意义上讲，所讨论的主题适用于由细胞外基质指令和完整性受损驱动的其他条件，导致进行性损伤和炎症。

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引用次数: 0

Alterations in the microenvironment of junctional epidermolysis bullosa keratinocytes: A gene expression study 大疱性结缔组织表皮松解角质形成细胞微环境的改变：一项基因表达研究。

IF 4.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.matbio.2024.11.005

Yao Wang , Maria Elena Hess , Yan Tan , Philipp R. Esser , Alexander Nyström , Melanie Boerries , Saliha Beyza Sayar , Cristina Has

Integrin α6β4 subunits and type XVII collagen are critical transmembrane proteins involved in cell-matrix adhesion in skin, while laminin 332 serves as their ligand in the basement membrane zone (BMZ). Those proteins contribute to the composition of hemidesmosomes (HDs) and pathogenic variants in their corresponding genes cause junctional epidermolysis bullosa (JEB). Although the genotype-phenotype relationships in JEB have been extensively studied, the pathogenetic changes of extracellular matrix (ECM) and cell-matrix adhesion resulting from gene mutations remain unclear. We conducted a global unbiased transcriptome analysis using bulk RNA sequencing (RNA-seq) on selected JEB donor-derived cell lines lacking integrin β4 subunit (ITGB4-), type XVII collagen (COL17-) and laminin β3 chain (LAMB3-), respectively. Additional JEB cell lines and JEB donor skin samples were used for validation of relevant findings. Collectively, the results revealed similar dysregulation patterns of ECM and focal adhesion (FAs) associated genes in ITGB4- and COL17- cell lines, while LAMB3- cells displayed a relatively opposite tendency. Importantly, key nodes in the dysregulated network were associated with ECM proteins involved in wound healing processes. Additionally, a group of inflammatory-associated genes was disclosed to be up-regulated in JEB keratinocytes and could not be normalized by the adhesion rescue. The functional assay further revealed the hierarchy of stable adhesion among mutant cell lines COL17->ITGB4->LAMB3-, which correlates with the severity of their clinical manifestations. Our results indicated a wound healing associated ECM and inflammatory microenvironment established by JEB keratinocytes.

整合素α6β4亚基和XVII型胶原是参与皮肤细胞-基质粘附的关键跨膜蛋白，而层粘连蛋白332是它们在基底膜区（BMZ）的配体。这些蛋白参与半粒酶（hd）的组成，其相应基因的致病变异导致大疱性结缔组织表皮松解症（JEB）。虽然人们已经广泛研究了JEB的基因型-表型关系，但基因突变导致的细胞外基质（ECM）和细胞-基质粘附的病理变化尚不清楚。我们使用大量RNA测序（RNA-seq）对选定的JEB供体来源的细胞系进行了全球无偏倚转录组分析，这些细胞系分别缺乏整合素β4亚基（ITGB4-）、XVII型胶原（COL17-）和层粘连蛋白β3链（LAMB3-）。额外的JEB细胞系和JEB供体皮肤样本用于验证相关发现。总的来说，结果显示ITGB4-和COL17-细胞系中ECM和局灶黏附（FAs）相关基因的失调模式相似，而LAMB3-细胞表现出相对相反的趋势。重要的是，失调网络中的关键节点与参与伤口愈合过程的ECM蛋白相关。此外，一组炎症相关基因在JEB角化细胞中被上调，并且不能通过粘附修复而正常化。功能分析进一步揭示了突变细胞系COL17->ITGB4->LAMB3-之间稳定粘附的等级关系，这种等级关系与其临床表现的严重程度有关。我们的结果表明，伤口愈合相关的ECM和炎症微环境是由JEB角化细胞建立的。

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引用次数: 0