Matrix Biology最新文献

{"title":"Hyaluronan and proteoglycan link protein 1 – A novel signaling molecule for rejuvenating aged skin","authors":"Zhicheng Fu ,&nbsp;Goowon Yang ,&nbsp;So Yoon Yun ,&nbsp;Ji Min Jang ,&nbsp;Hae Chan Ha ,&nbsp;In Chul Shin ,&nbsp;Moon Jung Back ,&nbsp;Yongwei Piao ,&nbsp;Dae Kyong Kim","doi":"10.1016/j.matbio.2024.08.009","DOIUrl":"10.1016/j.matbio.2024.08.009","url":null,"abstract":"<div><p>The skin seems to rejuvenate upon exposure to factors within the circulation of young organisms. Intrinsic factors that modulate skin aging are poorly understood. We used heterochronic parabiosis and aptamer-based proteomics to identify serum-derived rejuvenating factors. We discovered a novel extracellular function of hyaluronan and proteoglycan link protein 1 (HAPLN1). Its serum levels decreased with age, disturbing the integrity of the skin extracellular matrix, which is predominantly composed of collagen I and hyaluronan; levels of various markers, which decrease in aged skin, were significantly restored <em>in vivo</em> and <em>in vitro</em> by the administration of recombinant human HAPLN1 (rhHAPLN1). rhHAPLN1 protected transforming growth factor beta receptor 2 on the cell surface from endocytic degradation via mechanisms such as regulation of viscoelasticity, CD44 clustering. Moreover, rhHAPLN1 regulated the levels of nuclear factor erythroid 2–related factor 2, phosphorylated nuclear factor kappa B, and some cyclin-dependent kinase inhibitors such as p16 and p21. Therefore, rhHAPLN1 may act as a novel biomechanical signaling protein to rejuvenate aged skin.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 30-47"},"PeriodicalIF":4.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24001112/pdfft?md5=8ab084cfcac6cfeb61b9acc8b5b4bb38&pid=1-s2.0-S0945053X24001112-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127170","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":"Myocardial fibrosis from the perspective of the extracellular matrix: Mechanisms to clinical impact","authors":"Ida G. Lunde ,&nbsp;Karoline B. Rypdal ,&nbsp;Sophie Van Linthout ,&nbsp;Javier Diez ,&nbsp;Arantxa González","doi":"10.1016/j.matbio.2024.08.008","DOIUrl":"10.1016/j.matbio.2024.08.008","url":null,"abstract":"<div><p>Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and constitutes a central pathophysiological process that underlies tissue dysfunction, across organs, in multiple chronic diseases and during aging. Myocardial fibrosis is a key contributor to dysfunction and failure in numerous diseases of the heart and is a strong predictor of poor clinical outcome and mortality. The excess structural and matricellular ECM proteins deposited by cardiac fibroblasts, is found between cardiomyocytes (interstitial fibrosis), in focal areas where cardiomyocytes have died (replacement fibrosis), and around vessels (perivascular fibrosis). Although myocardial fibrosis has important clinical prognostic value, access to cardiac tissue biopsies for histological evaluation is limited. Despite challenges with sensitivity and specificity, cardiac magnetic resonance imaging (CMR) is the most applicable diagnostic tool in the clinic, and the scientific community is currently actively searching for blood biomarkers reflecting myocardial fibrosis, to complement the imaging techniques. The lack of mechanistic insights into specific pro- and anti-fibrotic molecular pathways has hampered the development of effective treatments to prevent or reverse myocardial fibrosis. Development and implementation of anti-fibrotic therapies is expected to improve patient outcomes and is an urgent medical need. Here, we discuss the importance of the ECM in the heart, the central role of fibrosis in heart disease, and mechanistic pathways likely to impact clinical practice with regards to diagnostics of myocardial fibrosis, risk stratification of patients, and anti-fibrotic therapy.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 1-22"},"PeriodicalIF":4.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114137","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":"Hyperglycemic environments directly compromise intestinal epithelial barrier function in an organoid model and hyaluronan (∼35 kDa) protects via a layilin dependent mechanism","authors":"Samreen Jatana ,&nbsp;Amina Abbadi ,&nbsp;Gail A. West ,&nbsp;András K. Ponti ,&nbsp;Manuel B. Braga-Neto ,&nbsp;Jordyn L. Smith ,&nbsp;Armando Marino-Melendez ,&nbsp;Belinda Willard ,&nbsp;Laura E. Nagy ,&nbsp;Carol de la Motte","doi":"10.1016/j.matbio.2024.08.007","DOIUrl":"10.1016/j.matbio.2024.08.007","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Metabolic syndrome and diabetes in obese individuals are strong risk factors for development of inflammatory bowel disease (IBD) and colorectal cancer. The pathogenic mechanisms of low-grade metabolic inflammation, including chronic hyperglycemic stress, in disrupting gut homeostasis are poorly understood. In this study, we sought to understand the impact of a hyperglycemic environment on intestinal barrier integrity and the protective effects of small molecular weight (35 kDa) hyaluronan on epithelial barrier function.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Intestinal organoids derived from mouse colon were grown in normal glucose media (5 mM) or high glucose media (25 mM) to study the impact of hyperglycemic stress on the intestinal barrier. Additionally, organoids were pretreated with 35 kDa hyaluronan (HA35) to investigate the effect of hyaluronan on epithelial barrier under high glucose stress. Immunoblotting as well as confocal imaging was used to understand changes in barrier proteins, quantitative as well as spatial distribution, respectively. Alterations in barrier function were measured using trans-epithelial electrical resistance and fluorescein isothiocyanate flux assays. Untargeted proteomics analysis was performed to elucidate mechanisms by which HA35 exerts a protective effect on the barrier. Intestinal organoids derived from receptor knockout mice specific to various HA receptors were utilized to understand the role of HA receptors in barrier protection under high glucose conditions.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;We found that high glucose stress decreased the protein expression as well as spatial distribution of two key barrier proteins, zona occludens-1 (ZO-1) and occludin. HA35 prevented the degradation or loss of ZO-1 and maintained the spatial distribution of both ZO-1 and occludin under hyperglycemic stress. Functionally, we also observed a protective effect of HA35 on the epithelial barrier under high glucose conditions. We found that HA receptor, layilin, was involved in preventing barrier protein loss (ZO-1) as well as maintaining spatial distribution of ZO-1 and occludin. Additionally, proteomics analysis showed that cell death and survival was the primary pathway upregulated in organoids treated with HA35 under high glucose stress. We found that XIAP associated factor 1 (Xaf1) was modulated by HA35 thereby regulating apoptotic cell death in the intestinal organoid system. Finally, we observed that spatial organization of both focal adhesion kinase (FAK) as well as F-actin was mediated by HA35 via layilin.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;Our results highlight the impact of hyperglycemic stress on the intestinal barrier function. This is of clinical relevance, as impaired barrier function has been observed in individuals with metabolic syndrome. Additionally, we demonstrate barrier protective effects of HA35 through its receptor layilin and modulation of cellular apoptosis under high glucose st","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 116-133"},"PeriodicalIF":4.5,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24001094/pdfft?md5=1c766d0c9cca2bc04493949f2a75f84f&pid=1-s2.0-S0945053X24001094-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074394","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":"Fibronectin isoforms promote postnatal skeletal development","authors":"Neha E.H. Dinesh ,&nbsp;Nissan Baratang ,&nbsp;Justine Rosseau ,&nbsp;Ronit Mohapatra ,&nbsp;Ling Li ,&nbsp;Ramshaa Mahalingam ,&nbsp;Kerstin Tiedemann ,&nbsp;Philippe M. Campeau ,&nbsp;Dieter P. Reinhardt","doi":"10.1016/j.matbio.2024.08.002","DOIUrl":"10.1016/j.matbio.2024.08.002","url":null,"abstract":"<div><p>Fibronectin (FN) is a ubiquitous extracellular matrix glycoprotein essential for the development of various tissues. Mutations in FN cause a unique form of spondylometaphyseal dysplasia, emphasizing its importance in cartilage and bone development. However, the relevance and functional role of FN during skeletal development has remained elusive. To address these aspects, we have generated conditional knockout mouse models targeting the cellular FN isoform in cartilage (cFNKO), the plasma FN isoform in hepatocytes (pFNKO), and both isoforms together in a double knockout (FNdKO). We used these mice to determine the relevance of the two principal FN isoforms in skeletal development from postnatal day one to the adult stage at two months.</p><p>We identified a distinct topological FN deposition pattern in the mouse limb during different gestational and postnatal skeletal development phases, with prominent levels at the resting and hypertrophic chondrocyte zones and in the trabecular bone. Cartilage-specific cFN emerged as the predominant isoform in the growth plate, whereas circulating pFN remained excluded from the growth plate and confined to the primary and secondary ossification centers. Deleting either isoform independently (cFNKO or pFNKO) yielded only relatively subtle changes in the analyzed skeletal parameters. However, the double knockout of cFN in the growth plate and pFN in the circulation of the FNdKO mice significantly reduced postnatal body weight, body length, and bone length. Micro-CT analysis of the adult bone microarchitecture in FNdKO mice exposed substantial reductions in trabecular bone parameters and bone mineral density. The mice also showed elevated bone marrow adiposity. Analysis of chondrogenesis in FNdKO mice demonstrated changes in the resting, proliferating and hypertrophic growth plate zones, consistent alterations in chondrogenic markers such as collagen type II and X, decreased apoptosis of hypertrophic chondrocytes, and downregulation of bone formation markers. Transforming growth factor-β1 and downstream phospho-AKT levels were significantly lower in the FNdKO than in the control mice, revealing a crucial FN-mediated regulatory pathway in chondrogenesis and bone formation.</p><p>In conclusion, the data demonstrate that FN is essential for chondrogenesis and bone development. Even though cFN and pFN act in different regions of the bone, both FN isoforms are required for the regulation of chondrogenesis, cartilage maturation, trabecular bone formation, and overall skeletal growth.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 86-102"},"PeriodicalIF":4.5,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24001045/pdfft?md5=223df76f43eebcd53906b944c05aa90b&pid=1-s2.0-S0945053X24001045-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005626","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":"Collagen VIII in vascular diseases","authors":"Qian Li ,&nbsp;Yin Tintut ,&nbsp;Linda L. Demer ,&nbsp;Roberto I. Vazquez-Padron ,&nbsp;Michelle P. Bendeck ,&nbsp;Jeffrey J. Hsu","doi":"10.1016/j.matbio.2024.08.006","DOIUrl":"10.1016/j.matbio.2024.08.006","url":null,"abstract":"<div><p>Collagens have dual functions in the extracellular matrix (ECM), acting as both structural components and signaling molecules in matricellular communication. Although collagen molecules share a common triple helix motif, the supramolecular organization helps classify them into nearly 30 different types of collagens. Collagen type VIII is a non-fibrillar, short-chain, network-forming collagen that is expressed throughout the vasculature. Collagen VIII expression is aberrant in cardiovascular, lung, and renal disease, as well as in several different types of cancer. It plays active roles in angiogenesis, vessel injury repair, maintenance of arterial compliance, atherosclerotic plaque formation and stability modulation, fibrosis, and ECM remodeling. This review presents an overview of the characteristics of collagen VIII in vascular-related disorders, from clinical significance to laboratory studies, with a major focus on highlighting the signaling properties of collagen VIII in the vascular ECM. The expression patterns of collagen VIII in human diseases and experimental animal models highlight the protein's important yet underexplored functions. A deeper understanding of its mechanisms and downstream signaling pathways may pave the way for translational and tissue engineering applications of collagen VIII.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 64-76"},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24001082/pdfft?md5=a798c7eb53554e941e24cc81d0b60dd5&pid=1-s2.0-S0945053X24001082-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001136","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":"Involvement of lysophosphatidic acid-LPA1-YAP signaling in healthy and pathological FAPs migration","authors":"Alexia Bock-Pereda ,&nbsp;Meilyn Cruz-Soca ,&nbsp;Felipe S. Gallardo ,&nbsp;Adriana Córdova-Casanova ,&nbsp;Cristian Gutierréz-Rojas ,&nbsp;Jennifer Faundez-Contreras ,&nbsp;Jerold Chun ,&nbsp;Juan Carlos Casar ,&nbsp;Enrique Brandan","doi":"10.1016/j.matbio.2024.08.005","DOIUrl":"10.1016/j.matbio.2024.08.005","url":null,"abstract":"<div><p>Skeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration.</p><p>Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA₁) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs.</p><p>Moreover, we found that FAPs derived from the <em>mdx</em>4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA₁ or YAP transcriptional coactivator activity in <em>mdx</em>4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA₁-YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 103-115"},"PeriodicalIF":4.5,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996813","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":"My scientific journey to and through extracellular matrix","authors":"Erkki Ruoslahti","doi":"10.1016/j.matbio.2024.08.003","DOIUrl":"10.1016/j.matbio.2024.08.003","url":null,"abstract":"<div><p>This article recounts my journey as a scientist in the early days of extracellular matrix research through the discovery of fibronectin, the RGD sequence as a key recognition motif in fibronectin and other adhesion proteins, and isolation and cloning of integrins. I also discuss more recent work on identification of molecular “zip codes” by <em>in vivo</em> screening of peptide libraries expressed on phage, which led us right back to RGD and integrins. Many disease-specific zip codes have turned out to be based on altered expression of extracellular matrix molecules and integrins. Homing peptides and antibodies recognizing zip code molecules are being used in drug delivery applications, some of which have advanced into clinical trials.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 57-63"},"PeriodicalIF":4.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996814","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":"Matrix stiffness increases energy efficiency of endothelial cells","authors":"Curtis T. Schunk ,&nbsp;Wenjun Wang ,&nbsp;Lindsey N. Sabo,&nbsp;Paul V. Taufalele,&nbsp;Cynthia A. Reinhart-King","doi":"10.1016/j.matbio.2024.08.004","DOIUrl":"10.1016/j.matbio.2024.08.004","url":null,"abstract":"<div><p>To form blood vessels, endothelial cells rearrange their cytoskeleton, generate traction stresses, migrate, and proliferate, all of which require energy. Despite these energetic costs, stiffening of the extracellular matrix promotes tumor angiogenesis and increases cell contractility. However, the interplay between extracellular matrix, cell contractility, and cellular energetics remains mechanistically unclear. Here, we utilized polyacrylamide substrates with various stiffnesses, a real-time biosensor of ATP, and traction force microscopy to show that endothelial cells exhibit increasing traction forces and energy usage trend as substrate stiffness increases. Inhibition of cytoskeleton reorganization via ROCK inhibition resulted in decreased cellular energy efficiency, and an opposite trend was found when cells were treated with manganese to promote integrin affinity. Altogether, our data reveal a link between matrix stiffness, cell contractility, and cell energetics, suggesting that endothelial cells on stiffer substrates can better convert intracellular energy into cellular traction forces. Given the critical role of cellular metabolism in cell function, our study also suggests that not only energy production but also the efficiency of its use plays a vital role in regulating cell behaviors and may help explain how increased matrix stiffness promotes angiogenesis.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 77-85"},"PeriodicalIF":4.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989377","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":"Skeletal pathology in mouse models of Gould syndrome is partially alleviated by genetically reducing TGFβ signaling","authors":"Cassandre Labelle-Dumais ,&nbsp;Courtney Mazur ,&nbsp;Serra Kaya ,&nbsp;Yoshihiro Obata ,&nbsp;Bryson Lee ,&nbsp;Claire Acevedo ,&nbsp;Tamara Alliston ,&nbsp;Douglas B. Gould","doi":"10.1016/j.matbio.2024.07.005","DOIUrl":"10.1016/j.matbio.2024.07.005","url":null,"abstract":"<div><p>Skeletal defects are hallmark features of many extracellular matrix (ECM) and collagen-related disorders. However, a biological function in bone has never been defined for the highly evolutionarily conserved type IV collagen. Collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form α1α1α2 (IV) heterotrimers that represent a fundamental basement membrane constituent present in every organ of the body, including the skeleton. <em>COL4A1</em> and <em>COL4A2</em> mutations cause Gould syndrome, a variable and clinically heterogenous multisystem disorder generally characterized by the presence of cerebrovascular disease with ocular, renal, and muscular manifestations. We have previously identified elevated TGFβ signaling as a pathological insult resulting from <em>Col4a1</em> mutations and demonstrated that reducing TGFβ signaling ameliorate ocular and cerebrovascular phenotypes in <em>Col4a1</em> mutant mouse models of Gould syndrome. In this study, we describe the first characterization of skeletal defects in <em>Col4a1</em> mutant mice that include a developmental delay in osteogenesis and structural, biomechanical and vascular alterations of mature bones. Using distinct mouse models, we show that allelic heterogeneity influences the presentation of skeletal pathology resulting from <em>Col4a1</em> mutations. Importantly, we found that TGFβ target gene expression is elevated in developing bones from <em>Col4a1</em> mutant mice and show that genetically reducing TGFβ signaling partially ameliorates skeletal manifestations. Collectively, these findings identify a novel and unsuspected role for type IV collagen in bone biology, expand the spectrum of manifestations associated with Gould syndrome to include skeletal abnormalities, and implicate elevated TGFβ signaling in skeletal pathogenesis in <em>Col4a1</em> mutant mice.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 1-13"},"PeriodicalIF":4.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000969/pdfft?md5=edf112416c9cb284a10412a4700b0ede&pid=1-s2.0-S0945053X24000969-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890716","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":"SERPINA3 is a marker of cartilage differentiation and is essential for the expression of extracellular matrix genes during early chondrogenesis","authors":"Matthew J Barter ,&nbsp;David A Turner ,&nbsp;Sarah J Rice ,&nbsp;Mary Hines ,&nbsp;Hua Lin ,&nbsp;Adrian M.D. Falconer ,&nbsp;Euan McDonnell ,&nbsp;Jamie Soul ,&nbsp;Maria del Carmen Arques ,&nbsp;G Nicholas Europe-Finner ,&nbsp;Andrew D. Rowan ,&nbsp;David A. Young ,&nbsp;David J. Wilkinson","doi":"10.1016/j.matbio.2024.07.004","DOIUrl":"10.1016/j.matbio.2024.07.004","url":null,"abstract":"<div><p>Serine proteinase inhibitors (serpins) are a family of structurally similar proteins which regulate many diverse biological processes from blood coagulation to extracellular matrix (ECM) remodelling. Chondrogenesis involves the condensation and differentiation of mesenchymal stem cells (MSCs) into chondrocytes which occurs during early development. Here, and for the first time, we demonstrate that one serpin, SERPINA3 (gene name <em>SERPINA3,</em> protein also known as alpha-1 antichymotrypsin), plays a critical role in chondrogenic differentiation. We observed that <em>SERPINA3</em> expression was markedly induced at early time points during <em>in vitro</em> chondrogenesis. We examined the expression of <em>SERPINA3</em> in human cartilage development, identifying significant enrichment of <em>SERPINA3</em> in developing cartilage compared to total limb, which correlated with well-described markers of cartilage differentiation. When <em>SERPINA3</em> was silenced using siRNA, cartilage pellets were smaller and contained lower proteoglycan as determined by dimethyl methylene blue assay (DMMB) and safranin-O staining. Consistent with this, RNA sequencing revealed significant downregulation of genes associated with cartilage ECM formation perturbing chondrogenesis. Conversely, <em>SERPINA3</em> silencing had a negligible effect on the gene expression profile during osteogenesis suggesting the role of SERPINA3 is specific to chondrocyte differentiation. The global effect on cartilage formation led us to investigate the effect of <em>SERPINA3</em> silencing on the master transcriptional regulator of chondrogenesis, SOX9. Indeed, we observed that SOX9 protein levels were markedly reduced at early time points suggesting a role for SERPINA3 in regulating SOX9 expression and activity. In summary, our data support a non-redundant role for SERPINA3 in enabling chondrogenesis via regulation of SOX9 levels.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 33-42"},"PeriodicalIF":4.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000957/pdfft?md5=0eaeee488a472aa9c27aae6f1154e131&pid=1-s2.0-S0945053X24000957-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890715","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}