Matrix Biology最新文献

Amelogenin proteolysis orchestrates functional amyloid pathways in enamel development 淀粉原蛋白水解在牙釉质发育过程中调控淀粉样蛋白通路

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-04-01 Epub Date: 2026-01-11 DOI: 10.1016/j.matbio.2026.01.001

Emerson Tavares de Sousa , Larry Ackerman , Johan Svensson Bonde , Stefan Habelitz , Yushi Bai

Amelogenin, the most abundant protein in developing enamel, self-assembles into supramolecular structures that serve as templates for apatite growth. Recent studies revealed that amelogenin nanoribbons exhibit hallmark features of functional amyloids, yet the molecular mechanisms governing their formation remain incompletely understood. Here, we combine atomic force microscopy, transmission electron microscopy, and spectroscopic analyses to define the assembly pathways of full-length amelogenin (rH174) alongside its major proteolytic products generated by metalloproteinase-20 (MMP20). We demonstrate that both rH174 and the C-terminally truncated rH146 follow a nucleated conformational conversion mechanism, progressing from spherical oligomers through proto-ribbons to ordered β-sheet–rich nanoribbons. rH174 assembly progresses slowly, displaying an extended lag phase and delayed maturation, whereas rH146 nucleates rapidly, completing these stages within a shorter timeframe. Cross-seeding of rH146 into rH174 monomers (1:10) eliminates the delay in rH174 assembly, rapidly driving the system into elongation and leading to an earlier stabilization of the assembly system. C-terminus–driven interactions in rH174 trigger secondary nucleation that evolves into bundled nanoribbons resembling enamel organization, a process largely absent in rH146. Cross-seeding, therefore, exemplifies the in vivo mechanism whereby nascent amelogenin is immediately added to existing nanoribbon scaffolds, a cooperative strategy that generates a heterogeneous matrix, coupling the ability of rapid nucleation and spatial organization. Unexpectedly, the MMP20 cleavage product – TRAP, which comprises the cross-beta assembly domain, does not form nanoribbons and diverts from the assembly pathway full-length amelogenin takes when hydrolyzed at the C-terminal. Hence, a MMP20-driven mechanism exists that could contribute to an enamel matrix that acts as a spacer and prevents early crystal fusion during the secretory stage of amelogenesis. These findings offer insights into a proteolysis-triggered assembly pathway that may reconcile long-standing supramolecular models of amelogenin and establish amelogenin as a vertebrate example of a functional amyloid that can be tuned to enable ordered enamel biomineralization.

成釉原蛋白是发育中的牙釉质中最丰富的蛋白质，它可以自我组装成超分子结构，作为磷灰石生长的模板。最近的研究表明，淀粉原纳米带具有功能性淀粉样蛋白的标志性特征，但控制其形成的分子机制仍不完全清楚。在这里，我们结合原子力显微镜、透射电子显微镜和光谱分析来确定全长淀粉原蛋白（rH174）及其由金属蛋白酶-20 （MMP20）产生的主要蛋白水解产物的组装途径。研究表明，rH174和c端截断的rH146都遵循成核构象转换机制，从球形低聚物经过原带到有序的富含β片的纳米带。rH174的组装过程缓慢，表现为滞后期延长和成熟期延迟，而rH146的成核速度很快，在较短的时间内完成这些阶段。将rH146交叉播种到rH174单体中（1:10），消除了rH174组装的延迟，迅速推动了系统的延伸，并导致了组装系统的早期稳定。在rH174中，c端驱动的相互作用触发二次成核，演变成类似珐琅质组织的捆绑纳米带，这一过程在rH146中基本不存在。因此，交叉播种体现了体内机制，即新生的淀粉原蛋白立即添加到现有的纳米带支架中，这是一种产生异质基质的合作策略，结合了快速成核和空间组织的能力。出乎意料的是，MMP20切割产物- TRAP，包含交叉β组装结构域，在c端水解时不形成纳米带，偏离全长淀粉原蛋白的组装途径。因此，存在一种mmp20驱动的机制，可以促进牙釉质基质作为间隔物，并在成釉发生的分泌阶段阻止早期晶体融合。这些发现为蛋白质水解引发的组装途径提供了新的见解，该途径可能会调和长期存在的淀粉原蛋白超分子模型，并将淀粉原蛋白建立为脊椎动物的功能性淀粉样蛋白，可以调节以实现有序的牙釉质生物矿化。

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引用次数: 0

Oxygen and TGF-β1 jointly regulate fibronectin and trophoblast behavior highlighting a potential role for matrix signaling in severe preeclampsia 氧和TGF-β1共同调节纤维连接蛋白和滋养细胞的行为，这突出了基质信号在重度子痫前期的潜在作用

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-04-01 Epub Date: 2026-01-31 DOI: 10.1016/j.matbio.2026.01.002

Felipe Gallardo , Delia I. Chiarello , Ivo Carrasco-Wong , Sebastián San Martín , Andrea Leiva , Rocío Salsoso , Jaime Gutiérrez

Fibronectin is a key component of the extracellular matrix whose abundance and organization depend on both environmental conditions and intracellular signaling. In this study we show that oxygen tension modifies the response of extravillous trophoblasts to TGF-β1 and thereby controls fibronectin output and matrix dependent cell behavior. TGF-β1 increased fibronectin transcripts and protein through SMAD3, p38 and AKT, while hypoxia altered this response by reducing fibronectin protein despite preserved mRNA and by shifting downstream phosphorylation toward SMAD3, ERK and p38 with reduced AKT activity. These changes influenced functional outcomes: fibronectin rich conditions and TGF-β1 suppressed invasion and supported endothelial-like organization, and interference with fibronectin integrin binding preserved invasiveness and prevented network formation. Analysis of placental tissue showed that the spatial pattern of fibronectin expression differs in severe preeclampsia, where fibronectin appears earlier along the trophoblast trajectory compared with normal pregnancy. Together, these findings define how oxygen and TGF-β1 jointly regulate fibronectin and trophoblast behavior, while descriptive observations in human placental tissue provide histological context consistent with these cellular responses and suggest a potential role for matrix-associated signaling in severe preeclampsia.

纤维连接蛋白是细胞外基质的重要组成部分，其丰度和组织取决于环境条件和细胞内信号。在这项研究中，我们发现氧张力改变了上皮外滋养细胞对TGF-β1的反应，从而控制了纤维连接蛋白的输出和基质依赖性细胞行为。TGF-β1通过SMAD3、p38和AKT增加了纤维连接蛋白的转录本和蛋白，而缺氧通过减少纤维连接蛋白而改变了这种反应，尽管保留了mRNA，并通过将下游磷酸化转移到SMAD3、ERK和p38而降低了AKT活性。这些变化影响功能结果：纤维连接蛋白丰富的条件和TGF-β1抑制侵袭并支持内皮样组织，干扰纤维连接蛋白整合素结合保持侵袭性并阻止网络形成。胎盘组织分析显示，重度子痫前期纤维连接蛋白表达的空间格局不同，与正常妊娠相比，纤维连接蛋白在滋养细胞轨迹上出现得更早。总之，这些发现定义了氧气和TGF-β1如何共同调节纤维连接蛋白和滋养细胞的行为，而在人类胎盘组织中的描述性观察提供了与这些细胞反应一致的组织学背景，并提示基质相关信号在严重子痫前期的潜在作用。

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引用次数: 0

An integrin α3β1-CSTF3 signaling axis regulates alternative polyadenylation of Mmp9 mRNA 整合素α3β1-CSTF3信号轴调控Mmp9 mRNA的选择性聚腺苷化

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-04-01 Epub Date: 2026-01-31 DOI: 10.1016/j.matbio.2026.01.003

Giesse Albeche Duarte , Ramon Bossardi Ramos , Lei Wu , Whitney M. Longmate , C. Michael DiPersio

The laminin-binding integrin α3β1 is highly expressed in epidermal keratinocytes, where it coordinates diverse cellular functions and gene expression during skin remodeling. Here, we show that α3β1-MEK/ERK signaling operates in vivo to promote proximal polyadenylation site (PAS) usage in the Mmp9 gene, generating a short, more stable mRNA transcript. Using mice with inducible, epidermis-specific α3 deletion, RNA in situ hybridization revealed that loss of α3β1 increased the long Mmp9 transcript in healing wounds and epidermal tumors. α3β1-MEK/ERK signaling in keratinocytes induced the expression of the cleavage stimulation factor CSTF3, a known regulator of alternative polyadenylation (APA), while CSTF3 knockdown shifted Mmp9 toward distal PAS usage. Moreover, α3 deletion reduced Cstf3 gene expression and altered APA in vivo. Genome-wide DaPars2 analysis identified α3β1-dependent APA across numerous genes, including some encoding components of the keratinocyte secretome. Together, these findings define a novel α3β1-MEK/ERK-CSTF3 axis that orchestrates post-transcriptional gene regulation through APA, revealing α3β1 as a potential target for wound and cancer therapies.

层粘连蛋白结合整合素α3β1在表皮角质形成细胞中高表达，在皮肤重塑过程中协调多种细胞功能和基因表达。在这里，我们发现α3β1-MEK/ERK信号在体内作用，促进Mmp9基因近端聚腺苷化位点（PAS）的使用，产生更短、更稳定的mRNA转录物。在诱导的表皮特异性α3缺失小鼠中，RNA原位杂交发现α3β1缺失增加了愈合伤口和表皮肿瘤中长链Mmp9的转录。角化细胞中的α3β1-MEK/ERK信号传导诱导了劈裂刺激因子CSTF3的表达，CSTF3是一种已知的选择性多聚腺苷化（APA）的调节因子，而CSTF3敲低将Mmp9转移到远端PAS的使用。此外，α3缺失降低了Cstf3基因在体内的表达，改变了APA。全基因组DaPars2分析发现α3β1依赖性APA跨越许多基因，包括角化细胞分泌组的一些编码成分。总之，这些发现定义了一个新的α3β1- mek /ERK-CSTF3轴，该轴通过APA协调转录后基因调控，揭示α3β1是伤口和癌症治疗的潜在靶点。

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引用次数: 0

Laminin-α2 is required for the maintenance of the myotendinous junction in vivo. 层粘连蛋白-α2是维持体内肌腱连接所必需的。

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-03-17 DOI: 10.1016/j.matbio.2026.03.003

Julia Schedel, Shuo Lin, Thomas Bock, Dominik Burri, Markus A Rüegg

The myotendinous junction (MTJ) is a critical interface between muscle fibers and tendons, essential for force transmission between muscle and bone. Laminin-α2, a key extracellular matrix (ECM) component, is strongly enriched at this interface. Mutations in the LAMA2 gene cause LAMA2-related muscular dystrophy (LAMA2 MD), an early-onset severe congenital muscular dystrophy. Here, we examined the MTJ in dy^W/dy^W mice, a mouse model for LAMA2 MD. We find a strong disruption of MTJ morphology, including altered muscle fiber tips, collagen XXII mislocalization, and reduced muscle tendon interface. As MTJ loading is altered in dy^W/dy^W mice and MTJ maintenance requires loading and unloading, we also examined MTJ structures upon denervation-induced unloading. While muscle fiber tip morphology resembled that of dy^W/dy^W mice, collagen XXII distribution was not affected and the muscle-tendon interface was preserved. Finally, proteomic profiling via laser capture microdissection and mass spectrometry revealed significant regional and global shifts in MTJ protein composition in dy^W/dy^W and denervated mice. Across both models, we identified integrin-associated remodeling as a shared response linked to the perturbed muscle fiber tip morphology. These findings demonstrate that laminin-α2 is required for MTJ stability, and that mechanical unloading contributes to the observed phenotype. Importantly, our results suggest that disruptions in MTJ structure and protein composition may contribute to the pathology observed in LAMA2 MD.

肌腱交界处（MTJ）是肌纤维和肌腱之间的关键界面，对肌肉和骨骼之间的力传递至关重要。层粘连蛋白-α2是细胞外基质（ECM）的关键成分，在该界面上富集。LAMA2基因突变导致LAMA2相关肌营养不良（LAMA2 MD），这是一种早发性严重先天性肌营养不良。在这里，我们检查了dyW/dyW小鼠（LAMA2 MD的小鼠模型）的MTJ。我们发现MTJ形态严重破坏，包括肌纤维尖端改变，胶原XXII错误定位，肌肉肌腱界面减少。由于dyW/dyW小鼠的MTJ负荷发生改变，MTJ的维持需要加载和卸载，我们还研究了去神经诱导卸载时的MTJ结构。肌纤维尖端形态与dyW/dyW小鼠相似，胶原XXII分布不受影响，肌-肌腱界面保存完好。最后，通过激光捕获显微解剖和质谱分析的蛋白质组学分析显示，dyW/dyW和去神经小鼠MTJ蛋白组成在区域和全局上发生了显著的变化。在这两种模型中，我们发现整合素相关的重塑是与受干扰的肌纤维尖端形态相关的共同反应。这些发现表明层粘连蛋白-α2是MTJ稳定性所必需的，而机械卸载有助于观察到的表型。重要的是，我们的研究结果表明，MTJ结构和蛋白质组成的破坏可能有助于LAMA2 MD中观察到的病理。

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引用次数: 0

In Memoriam: Richard O. Hynes (1944-2026) 纪念：理查德·o·海因斯（1944-2026）

IF 6.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-03-13 DOI: 10.1016/j.matbio.2026.03.002

C. Michael DiPersio, Deane F. Mosher, Alexandra Naba, Jean E. Schwarzbauer

引用次数: 0

Observations of dystrophic epidermolysis bullosa patients with collagen VII NC2 truncation provide new insights into anchoring fibril assembly 观察营养不良大疱性表皮松解症患者的胶原VII NC2截短提供了锚定纤维组装的新见解

IF 6.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-03-04 DOI: 10.1016/j.matbio.2026.03.001

Neha S. Momin, I. Sinem Bagci, John A. Dolorito, Sara F. Tufa, Pragya Tripathi, Kunju J. Sridhar, Douglas R. Keene, M. Peter Marinkovich

Type VII collagen (C7) assembles into anchoring fibrils (AF) which are basement membrane zone (BMZ) structures that reinforce dermal-epidermal cohesion. Mutations in COL7A1, which encodes C7, cause dystrophic epidermolysis bullosa (DEB), a blistering disorder characterized by skin fragility. C7 consists of a central collagenous domain flanked by non-collagenous NC1 and NC2 regions. During AF assembly, C-proteinase-mediated cleavage of the NC2 domain enables anti-parallel dimer formation, followed by C7 lateral association into mature, banded AFs that loop through the dermis to anchor the epidermis. Here, we report two DEB patients expressing near full-length C7 truncated just proximal to the C-proteinase cleavage site (amino acids 2814-2843), which precludes anti-parallel dimerization. Despite this, electron microscopy revealed abundant, banded AFs, consistent with lateral association, but the fibrils failed to loop and reinsert into the BMZ. These findings demonstrate that C7 lateral association can occur independently of anti-parallel dimer formation. This work also highlights the importance of AF looping in maintaining skin integrity and how specific COL7A1 mutations may impact fibril architecture and clinical phenotype.

VII型胶原（C7）组装成锚定原纤维（AF），这是基膜带（BMZ）结构，加强真皮与表皮的凝聚力。编码C7的COL7A1突变可导致营养不良性大疱性表皮松解症（DEB），这是一种以皮肤脆弱为特征的起泡疾病。C7由一个中央胶原区组成，两侧是非胶原的NC1和NC2区。在AF组装过程中，c蛋白酶介导的NC2结构域的裂解使反平行二聚体形成，随后C7横向结合成成熟的带状AF，穿过真皮层固定在表皮上。在这里，我们报告了两例DEB患者表达接近全长的C7，截断刚好在c蛋白酶切割位点（氨基酸2814-2843）的近端，这排除了反平行二聚化。尽管如此，电子显微镜显示大量带状AFs，与侧结合一致，但原纤维未能形成环并重新插入BMZ。这些发现表明C7横向结合可以独立于反平行二聚体的形成而发生。这项工作还强调了AF环在维持皮肤完整性方面的重要性，以及特定COL7A1突变如何影响原纤维结构和临床表型。

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引用次数: 0

Furin-like cleavage at the C1-C2 linker region of the ⍺3 chain is not required for collagen VI assembly 在C1-C2连接区，类似于furin的切割对于胶原VI的组装是不需要的

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-02-01 Epub Date: 2025-11-15 DOI: 10.1016/j.matbio.2025.11.003

Arthur Lauri Pasanen-Zentz , Mengjie Zhu , Sebastian Schmitz , Nitin George Eapen , Matthias Pzryklenk , Fabian Metzen , Karina Hadrian , Matthias Mörgelin , Uwe Hansen , Branko Zevnik , Simon E Tröder , Felix Bock , Catherine Moali , Marcus Krüger , Manuel Koch , Mats Paulsson , Raimund Wagener , Alvise Schiavinato

Collagen VI is a heterotrimeric, ubiquitously expressed microfibrillar collagen with a complex intracellular and extracellular assembly process. In addition to a short collagenous region, it is primarily composed of von Willebrand factor A (VWA) domains. Notably, only the C-terminal end of the α3 chain contains other domain types, including a Kunitz-like C5 domain, which has been reported to be necessary for microfibril formation, to function as a matrikine and exhibit biomarker properties. This region of the α3 chain undergoes proteolytic processing, with cleavage sites identified for proprotein convertases, matrix metalloproteinases (MMPs), and bone morphogenetic protein 1 (BMP1). Cleavage by furin-like convertases results in the generation of a mature collagen VI α3 chain lacking its 70 kDa C2-C5 domains. Here, we provide the first characterization of the functional significance of the furin-like cleavage site, demonstrating that while it is constitutively used, it is not essential for collagen VI assembly, microfibril formation, or skeletal muscle function under physiological conditions, likely due to the presence of redundant cleavage sites. We also present an initial characterization of the biological activity of the released fragments on myoblast cultures showing that they do not affect C2C12 myoblast behaviour or differentiation. These findings deepen our understanding of α3 chain processing and highlight its potential significance for collagen VI assembly and function, including the generation of peptides with potential biomarker and biological activity properties.

胶原VI是一种异三聚体，普遍表达的微纤维胶原蛋白，具有复杂的细胞内和细胞外组装过程。除了一个短的胶原区外，它主要由血管性血友病因子a （VWA）结构域组成。值得注意的是，只有α3链的c末端含有其他结构域类型，包括库尼茨样的C5结构域，该结构域被报道为微纤维形成所必需的，作为基质因子并表现出生物标志物的特性。α3链的这一区域发生蛋白水解加工，其裂解位点被鉴定为蛋白转化酶、基质金属蛋白酶（MMPs）和骨形态发生蛋白1 （BMP1）。通过类似于furin的转化酶的切割，导致成熟的胶原VI α3链缺乏其70 kDa的C2-C5结构域。在这里，我们首次对类糠蛋白裂解位点的功能意义进行了表征，证明了虽然它是组成性使用的，但在生理条件下，它对胶原VI组装、微纤维形成或骨骼肌功能并不是必需的，这可能是由于存在冗余的裂解位点。我们还初步表征了释放片段在成肌细胞培养物上的生物活性，表明它们不影响C2C12成肌细胞的行为或分化。这些发现加深了我们对α3链加工的理解，并强调了其对胶原VI组装和功能的潜在意义，包括产生具有潜在生物标志物和生物活性特性的肽。

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引用次数: 0

Follow the science: How fat cells taught us about scarring and ECM homeostasis 遵循科学：脂肪细胞如何教会我们疤痕和ECM稳态

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-02-01 Epub Date: 2025-12-15 DOI: 10.1016/j.matbio.2025.12.003

Valerie Horsley

This article describes the journey of my laboratory team as we became fascinated with the dynamic changes that occurred to adipose tissue in the skin during tissue injury and fibrosis. I discuss how lineage tracing and molecular manipulation of adipocyte lineage cells led us to discover novel ways that fat cells contribute to ECM homeostasis in the skin. This work revealed the importance of adipocyte plasticity and cell communication during tissue repair and as they respond to fibrotic stimuli.

这篇文章描述了我的实验室团队的旅程，因为我们对组织损伤和纤维化期间皮肤脂肪组织发生的动态变化着迷。我讨论了谱系追踪和脂肪细胞谱系细胞的分子操作如何引导我们发现脂肪细胞促进皮肤ECM稳态的新途径。这项工作揭示了脂肪细胞可塑性和细胞通讯在组织修复过程中的重要性，以及它们对纤维化刺激的反应。

引用次数: 0

Zebrafish col4a1 loss-of-function models mirror key neurovascular and ocular features of COL4A1/A2 syndrome and enable human variants assessment in vivo 斑马鱼col4a1功能丧失模型反映了col4a1 /A2综合征的关键神经血管和眼部特征，并能够在体内评估人类变异

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-02-01 Epub Date: 2025-11-15 DOI: 10.1016/j.matbio.2025.11.004

Graziamaria Paradisi , Valeria Bonavolontà , Martina Venditti , Giulia Fasano , Catia Pedalino , Filippo Del Bene , Marco Tartaglia , Antonella Lauri

Pathogenic variants in COL4A1 and COL4A2, encoding type IV collagen α1 and α2 chains—core components of all basement membranes—cause a multisystem disorder with variable expressivity. Affected individuals commonly present with cerebral small vessel disease (cSVD), unmanageable intracerebral haemorrhage (ICH), drug-resistant epilepsy, microphthalmia, and congenital cataract. Severe phenotypes are often linked to glycine substitutions that disrupt α1/α2 heterotrimer assembly, though insertions, deletions, and haploinsufficiency seem to also be pathogenic. Limited insight into collagen IV α1 and α2 biology and how specific variants affect their functions—coupled with a lack of rapid in vivo assays for functional variants classification—hampers patient stratification and therapy development. Here, we established and characterized two complementary col4a1 knockdown (KD) models in zebrafish. Taking advantages of their transparency and rapid development we set-up in vivo assays for neurovascular and ocular phenotyping. Both models reproduced key features of human disease, including ventriculomegaly, vascular fragility with spontaneous and trauma-induced ICH, microphthalmia, and cataracts. Notably, expression of human wild-type COL4A1 partially rescued most of the observed defects, while pathogenic glycine-substitution variants failed to do so. These findings validate col4a1 KD in zebrafish as a robust in vivo model of some aspects of COL4A1/A2 syndrome, highlighting a conserved role of collagen IV α1 in neurovascular and ocular development. Our results also support haploinsufficiency as a contributing pathogenic mechanism, alongside dominant-negative effects. This work lays the foundation for the use of zebrafish to support rapid COL4A1 and COL4A2 variants pathogenicity assessment and mechanistic studies, with the potential to accelerate development of targeted therapies.

COL4A1和COL4A2的致病变异，编码IV型胶原α1和α2链-所有基底膜的核心成分-导致具有可变表达的多系统疾病。受影响的个体通常表现为脑血管疾病（cSVD），难以控制的脑出血（ICH），耐药癫痫，小眼和先天性白内障。严重的表型通常与破坏α1/α2异源三聚体组装的甘氨酸取代有关，尽管插入、缺失和单倍不足似乎也是致病的。对IV型胶原α1和α2生物学以及特异性变异如何影响其功能的了解有限，再加上缺乏快速的体内功能变异分类分析，阻碍了患者分层和治疗发展。在这里，我们在斑马鱼中建立并表征了两个互补的col4a1敲低（KD）模型。利用其透明性和快速发展的优势，我们建立了神经血管和眼部表型的体内分析。这两种模型都再现了人类疾病的关键特征，包括脑室肿大、自发性和外伤性脑出血引起的血管易碎性、小眼和白内障。值得注意的是，人类野生型COL4A1的表达部分挽救了大多数观察到的缺陷，而致病性甘氨酸替代变体却没有做到这一点。这些发现证实了斑马鱼的col4a1 KD是col4a1 /A2综合征某些方面的强大体内模型，强调了胶原IV α1在神经血管和眼部发育中的保守作用。我们的研究结果也支持单倍不足作为致病机制，以及显性负作用。这项工作为利用斑马鱼支持COL4A1和COL4A2变异的快速致病性评估和机制研究奠定了基础，并有可能加速靶向治疗的开发。

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引用次数: 0

Liver-derived, circulating plasma fibronectin regulates trabecular bone mass and bone formation in adult male mice and its levels in sera associates with bone density in aging men 肝脏来源的循环血浆纤维连接蛋白调节成年雄性小鼠的骨小梁骨量和骨形成，以及其在血清中的水平与老年男性骨密度的关系

IF 4.8 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Matrix Biology

Pub Date : 2026-02-01 Epub Date: 2025-12-07 DOI: 10.1016/j.matbio.2025.12.001

Mahdokht Mahmoodi , Claudie Berger , Mir-Hamed Nabavi , Yongjun Xiao , Lucie Canaff , Monica Pata , Jingjing Li , Mathieu Ferron , Monzur Murshed , David Goltzman , Suzanne N. Morin , Mari T. Kaartinen

Plasma fibronectin is a liver-derived glycoprotein that circulates at relatively high concentration and accumulates in tissues to form ECM. The role of plasma fibronectin in osteoblastogenesis, bone formation and remodeling has been suggested by many in vitro studies, but in vivo mouse models have not confirmed its role in bone formation and maintenance of bone mass. In this study we have performed skeletal phenotyping of adult, 6-month-old male and female, hepatocyte-specific fibronectin knockout (Fn1-/-ALB) mice. We report that mice have a significant loss of bone mass as analyzed by micro-Computed Tomography (μCT) of the tibial and vertebral trabecular bone. Dual-energy X-ray absorptiometry of the vertebral bone showed a decrease in bone mineral density. Histomorphometric analysis of bone cell numbers in vertebral bone showed a significant decrease in osteoblasts and in mineral apposition rates; there was also a significant reduction of a serum marker of bone formation (PINP), demonstrating an important role for plasma fibronectin in osteoblastogenesis in adult mice. The phenotype was observed only in male mice. Osteoclastogenesis was not affected. Analysis of plasma fibronectin levels in human osteoporosis via Canadian Multicentre Osteoporosis Study (CaMos) biobank demonstrated that circulating plasma fibronectin levels were significantly higher in men versus women aged 50 and over. Male osteoporotic patients showed significantly lower plasma fibronectin levels which correlated with low bone mineral density values, and with reduced T-scores of the lumbar spine (L1-4, p=0.0088), and of the total hip (p=0.0066) strongly suggesting an association between pFN levels and fracture risk in men.

血浆纤维连接蛋白是一种来源于肝脏的糖蛋白，它以较高的浓度循环并在组织中积累形成ECM。血浆纤维连接蛋白在成骨细胞发生、骨形成和重塑中的作用已被许多体外研究提出，但在小鼠体内模型中尚未证实其在骨形成和骨量维持中的作用。在这项研究中，我们对成年、6个月大的雄性和雌性肝细胞特异性纤维连接蛋白敲除（Fn1-/- alb）小鼠进行了骨骼表型分析。我们报道，通过胫骨和椎小梁骨的微计算机断层扫描（μCT）分析，小鼠骨量明显减少。双能x线骨密度测量显示骨密度降低。椎体骨的组织形态学分析显示成骨细胞和矿物质附着率显著降低；血清骨形成标志物（PINP）也显著降低，表明血浆纤维连接蛋白在成年小鼠成骨细胞形成中起重要作用。该表型仅在雄性小鼠中观察到。破骨细胞生成未受影响。通过加拿大多中心骨质疏松研究（CaMos）生物库对人类骨质疏松症患者血浆纤维连接蛋白水平的分析表明，50岁及以上男性的循环血浆纤维连接蛋白水平明显高于女性。男性骨质疏松患者血浆纤维连接蛋白水平明显降低，这与低骨密度值、腰椎（L1-4, p=0.0088）和全髋关节（p=0.0066）的t评分降低相关，强烈提示pFN水平与男性骨折风险之间存在关联。

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引用次数: 0