Matrix Biology最新文献

{"title":"Mysteries of the collagen triple helix","authors":"Hans Peter Bächinger ,&nbsp;Sergei P. Boudko","doi":"10.1016/j.matbio.2025.02.003","DOIUrl":"10.1016/j.matbio.2025.02.003","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"137 ","pages":"Pages 12-18"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433939","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}

{"title":"Inhibition of the MRTF-A/SRF signaling axis alleviates vocal fold scarring","authors":"Ryan M. Friedman ,&nbsp;Huy D. Truong ,&nbsp;Matthew R. Aronson ,&nbsp;Elizabeth A. Brown ,&nbsp;Marco Angelozzi ,&nbsp;Jeffrey F. Chen ,&nbsp;Karen B. Zur ,&nbsp;Véronique Lefebvre ,&nbsp;Riccardo Gottardi","doi":"10.1016/j.matbio.2025.02.004","DOIUrl":"10.1016/j.matbio.2025.02.004","url":null,"abstract":"<div><div>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 <em>in vitro</em>. 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 <em>ACTA2</em>. 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.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"137 ","pages":"Pages 1-11"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433802","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}

{"title":"Role of syndecan-4 in angiogenesis and vasculogenic mimicry in triple negative breast cancer cells","authors":"Jessica Oyie Sousa Onyeisi ,&nbsp;Heba M. El-Shorafa ,&nbsp;Burkhard Greve ,&nbsp;Martin Götte","doi":"10.1016/j.matbio.2025.02.002","DOIUrl":"10.1016/j.matbio.2025.02.002","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 127-133"},"PeriodicalIF":4.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dystrophic epidermolysis bullosa - From biochemistry to interventions","authors":"Alexander Nyström","doi":"10.1016/j.matbio.2025.02.001","DOIUrl":"10.1016/j.matbio.2025.02.001","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 111-126"},"PeriodicalIF":4.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143369736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations in the microenvironment of junctional epidermolysis bullosa keratinocytes: A gene expression study","authors":"Yao Wang ,&nbsp;Maria Elena Hess ,&nbsp;Yan Tan ,&nbsp;Philipp R. Esser ,&nbsp;Alexander Nyström ,&nbsp;Melanie Boerries ,&nbsp;Saliha Beyza Sayar ,&nbsp;Cristina Has","doi":"10.1016/j.matbio.2024.11.005","DOIUrl":"10.1016/j.matbio.2024.11.005","url":null,"abstract":"<div><div>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-&gt;ITGB4-&gt;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.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 12-23"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cleavage of Cartilage Oligomeric Matrix Protein (COMP) by ADAMTS4 generates a neoepitope associated with osteoarthritis and other forms of degenerative joint disease","authors":"Rens de Groot ,&nbsp;Patricia Badía Folgado ,&nbsp;Kazuhiro Yamamoto ,&nbsp;Daniel R. Martin ,&nbsp;Christopher D. Koch ,&nbsp;Danielle Debruin ,&nbsp;Sophie Blagg ,&nbsp;Alexander F. Minns ,&nbsp;Sumit Bhutada ,&nbsp;Josefin Ahnström ,&nbsp;Jonathan Larkin ,&nbsp;Anders Aspberg ,&nbsp;Patrik Önnerfjord ,&nbsp;Suneel S. Apte ,&nbsp;Salvatore Santamaria","doi":"10.1016/j.matbio.2024.12.005","DOIUrl":"10.1016/j.matbio.2024.12.005","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a highly prevalent joint disease, affecting millions of people worldwide and characterized by degradation of articular cartilage, subchondral bone remodeling and low-grade inflammation, leading to pain, stiffness and disability. Cartilage Oligomeric Matrix Protein (COMP) is a major structural component of cartilage and its degradation has been proposed as a marker of OA severity/progression. Several proteases cleave COMP <em>in vitro</em>, however, it is unclear which of these COMPase activities is prevalent in an osteoarthritic joint. Here, using purified recombinant proteins, we show that A Disintegrin And Metalloproteinase with Thrombospondin motifs 4 (ADAMTS4) is the most potent COMPase, followed by ADAMTS1. Using liquid chromatography-tandem mass spectrometry, we identified several novel cleavage sites in COMP resulting from ADAMTS4 and ADAMTS1 activity. Cleavage at S⁷⁷-V⁷⁸ disrupted the pentameric organization of COMP and generated a neopeptide previously identified in the synovial fluid of OA patients. Immunoblots with anti-QQS⁷⁷ antibodies confirmed that ADAMTS4 efficiently cleaved this peptide bond. By analyzing five ADAMTS4 variants, we found that the C-terminal spacer domain is strictly necessary for COMPase activity and identified the specific residues involved in the interaction with COMP. An inhibitory anti-ADAMTS4 antibody significantly decreased generation of the COMP QQS⁷⁷ neoepitope in human OA cartilage explants, implicating ADAMTS4 as a key protease in generating the QQS⁷⁷ neopeptides in OA. Since another major ADAMTS4 substrate is aggrecan, the most abundant proteoglycan in cartilage, these findings highlight that, by cleaving both COMP and aggrecan, ADAMTS4 may play a crucial role in modulating the structural integrity of cartilage.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 106-124"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using load to improve tendon/ligament tissue engineering and develop novel treatments for tendinopathy","authors":"Kenneth T. Tam ,&nbsp;Keith Baar","doi":"10.1016/j.matbio.2024.12.001","DOIUrl":"10.1016/j.matbio.2024.12.001","url":null,"abstract":"<div><div>Tendon and ligament injuries are highly prevalent but heal poorly, even with proper care. Restoration of native tissue function is complicated by the fact that these tissues vary anatomically in terms of their mechanical properties, composition, and structure. These differences develop as adaptations to diverse mechanical demands; however, pathology may alter the loads placed on the tissue. Musculoskeletal loads can be generally categorized into tension, compression, and shear. Each of these regulate distinct molecular pathways that are involved in tissue remodeling, including many of the canonical tenogenic genes. In this review, we provide a perspective on the stage-specific regulation of mechanically sensitive pathways during development and maturation of tendon and ligament tissue, including scleraxis, mohawk, and others. Furthermore, we discuss structural features of healing and diseased tendon that may contribute to aberrant loading profiles, and how the associated disturbance in molecular signaling may contribute to incomplete healing or the formation of degenerative phenotypes. The perspectives provided here draw from studies spanning <em>in vitro</em>, animal, and human experiments of healthy and diseased tendon to propose a more targeted approach to advance rehabilitation, orthobiologics, and tissue engineering.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 39-54"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional transfer of integrin co-receptor CD98hc by small extracellular vesicles improves wound healing in vivo","authors":"Floriane S. Tissot ,&nbsp;Soline Estrach ,&nbsp;Laetitia Seguin ,&nbsp;Laurence Cailleteau ,&nbsp;Ayelet Levy ,&nbsp;Daniel Aberdam ,&nbsp;Chloé C. Féral","doi":"10.1016/j.matbio.2024.12.006","DOIUrl":"10.1016/j.matbio.2024.12.006","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) mediate intercellular communication. EVs are composed of a lipid bilayer and contain cytosolic proteins and RNAs. Studies highlight EVs striking functions in cell-cell crosstalk. Here, we found that small EVs can transfer functional signaling molecules through their lipid bilayer and participate in skin homeostasis. We identified a transmembrane protein CD98hc (a.k.a. SLC3A2), an integrin co-receptor (Itgb1 and Itgb3), implicated in epidermis homeostasis via its capacity in regulating extracellular matrix, as an important mediator of EV-based intercellular communication <em>in vivo</em>. We first demonstrated that healthy dermal fibroblasts produced and secreted EVs bearing characteristic of exosome-like small EVs (sEVs). We show that CD98hc, Itgb1 co-receptor, is present at the surface of sEVs, transferred and stabilized at the plasma membrane. The transferred complex is functional on recipient cells both <em>in vitro</em> and <em>in vivo</em>. Indeed, treatment with sEVs from WT, but not KO cells rescued migratory defects observed either in CD98hc KO dermal fibroblasts or in keratinocytes <em>in vitro</em>. Furthermore, injection of sEVs at the margins of wound in impaired wound healing mouse models (epidermal CD98hc KO mice exhibiting healing defect and elderly mice) improved wound closure <em>in vivo</em>. CD98hc complex transferred from sEVs remained stabilized at least 7 days after injection. Thus, our findings reveal that <em>in vivo</em> treatment with sEVs containing integrin co-receptor CD98hc could improve multiple skin afflictions.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 99-105"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A CNA-35-based high-throughput fibrosis assay reveals ORAI1 as a regulator of collagen release from pancreatic stellate cells","authors":"Rieke Schleinhege ,&nbsp;Ilka Neumann ,&nbsp;Andrea Oeckinghaus ,&nbsp;Albrecht Schwab ,&nbsp;Zoltán Pethő","doi":"10.1016/j.matbio.2024.12.004","DOIUrl":"10.1016/j.matbio.2024.12.004","url":null,"abstract":"<div><h3>Rationale</h3><div>Pancreatic stellate cells (PSCs) produce a collagen-rich connective tissue in chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Ca²⁺-permeable ion channels such as ORAI1 are known to affect PSC proliferation and myofibroblastic phenotype. However, it is unknown whether these channels play a role in collagen secretion.</div></div><div><h3>Methods</h3><div>Using the PSC cell line PS-1, we characterized their cell-derived matrices using staining, mass spectroscopy, and cell migration assays. We developed and validated a high-throughput <em>in vitro</em> fibrosis assay to rapidly determine collagen quantity either with Sirius Red or, in the optimized version, with the collagen-binding peptide CNA-35-tdTomato. We assessed collagen deposition upon stimulating cells with transforming growth factor β1 (TGF-β1) and/or vitamin C without or with ORAI1 modulation. Orai1 expression was assessed by immunohistochemistry in the fibrotic tumor tissue of a murine PDAC model (KPfC).</div></div><div><h3>Results</h3><div>We found that TGF-β1 and vitamin C promote collagen deposition from PSCs. We used small interfering RNA (siRNA) and the inhibitor Synta-66 to demonstrate that ORAI1 regulates collagen secretion of PSCs but not NIH-3T3 fibroblasts. Physiological levels of vitamin C induce a drastic increase of the intracellular [Ca²⁺] in PSCs, with Synta-66 inhibiting Ca²⁺ influx. Lastly, we revealed Orai1 expression in cancer-associated fibroblasts (CAFs) in murine PDAC (KPfC) samples.</div></div><div><h3>Conclusion</h3><div>In conclusion, our study introduces a robust <em>in vitro</em> assay for fibrosis and identifies ORAI1 as being engaged in PSC-driven fibrosis.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 70-86"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrillin-1 G234D mutation in the hybrid1 domain causes tight skin associated with dysregulated elastogenesis and increased collagen cross-linking in mice","authors":"ASM Sakhawat Hossain ,&nbsp;Maria Thea Rane Dela Cruz Clarin ,&nbsp;Kenichi Kimura ,&nbsp;George Biggin ,&nbsp;Yuki Taga ,&nbsp;Koichiro Uto ,&nbsp;Ayana Yamagishi ,&nbsp;Eri Motoyama ,&nbsp;Narenmandula ,&nbsp;Kazunori Mizuno ,&nbsp;Chikashi Nakamura ,&nbsp;Keiichi Asano ,&nbsp;Sumio Ohtsuki ,&nbsp;Tomoyuki Nakamura ,&nbsp;Sachiko Kanki ,&nbsp;Clair Baldock ,&nbsp;Erna Raja ,&nbsp;Hiromi Yanagisawa","doi":"10.1016/j.matbio.2024.11.006","DOIUrl":"10.1016/j.matbio.2024.11.006","url":null,"abstract":"<div><div>Fibrillin-1, an extracellular matrix (ECM) protein encoded by the <em>FBN1</em> gene, serves as a microfibril scaffold crucial for elastic fiber formation and homeostasis in pliable tissue such as the skin. Aside from causing Marfan syndrome, some mutations in <em>FBN1</em> result in scleroderma, marked by hardened and thicker skin which limits joint mobility. Here, we describe a tight skin phenotype in the <em>Fbn1</em>^G234D/G234D mice carrying a corresponding variant of <em>FBN1</em> in the hybrid1 domain that was identified in a patient with familial aortic dissection. Unlike scleroderma, skin thickness and collagen fiber abundance do not change in the <em>Fbn1</em>^G234D/G234D mutant skin. Instead, increased collagen cross-links were observed. In addition, short elastic fibers were sparsely located underneath the panniculus muscle layer, and an abundance of thin, aberrant elastic fibers was increased within the subcutaneous fascia, which may have tightened skin attachment to the underlying skeletal muscle. Structurally, <em>Fbn1</em>^G234D/G234D microfibrils have a disrupted shoulder region that shares similarities with hybrid1 deletion mutant microfibrils. We then demonstrate the consequence of fibrillin-1 G234D mutation on dermal fibroblast functions. Mutant primary fibroblasts produce fewer elastic fibers, exhibit slower migration and increased cell stiffness. Moreover, secretome from mutant fibroblasts are marked by enhanced secretion of ECM, ECM-modifying enzymes, proteoglycans and cytokines, which are pro-tissue repair/fibrogenic. The transcriptome of mutant fibroblasts displays an increased expression of myogenic developmental and immune-related genes. Our study proposes that imbalanced ECM homeostasis due to a fibrillin-1 G234D mutation impacts fibroblast properties with potential ramifications on skin function.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 24-38"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}