Matrix Biology最新文献

{"title":"Loss of 3-O-sulfotransferase enzymes, Hs3st3a1 and Hs3st3b1, reduces kidney and glomerular size and disrupts glomerular architecture","authors":"","doi":"10.1016/j.matbio.2024.06.006","DOIUrl":"10.1016/j.matbio.2024.06.006","url":null,"abstract":"<div><p>Heparan sulfate (HS) is an important component of the kidney anionic filtration barrier, the glomerular basement membrane (GBM). HS chains attached to proteoglycan protein cores are modified by sulfotransferases in a highly ordered series of biosynthetic steps resulting in immense structural diversity due to negatively charged sulfate modifications. 3-<em>O</em>-sulfation is the least abundant modification generated by a family of seven isoforms but creates the most highly sulfated HS domains. We analyzed the kidney phenotypes in the <em>Hs3st3a1, Hs3st3b1</em> and <em>Hs3st6</em> -knockout (KO) mice, the isoforms enriched in kidney podocytes. Individual KO mice show no overt kidney phenotype, although <em>Hs3st3b1</em> kidneys were smaller than wildtype (WT). Furthermore, <em>Hs3st3a1^-/-; Hs3st3b1^-/-</em> double knockout (DKO) kidneys were smaller but also had a reduction in glomerular size relative to wildtype (WT). Mass spectrometry analysis of kidney HS showed reduced 3-<em>O</em>-sulfation in <em>Hs3st3a1^-/-</em> and <em>Hs3st3b1^-/-</em>, but not in <em>Hs3st6^-/-</em> kidneys. Glomerular HS showed reduced HS staining and reduced ligand-and-carbohydrate engagement (LACE) assay, a tool that detects changes in binding of growth factor receptor-ligand complexes to HS. Interestingly, DKO mice have increased levels of blood urea nitrogen, although no differences were detected in urinary levels of albumin, creatinine and nephrin. Finally, transmission electron microscopy showed irregular and thickened GBM and podocyte foot process effacement in the DKO compared to WT. Together, our data suggest that loss of 3-<em>O</em>-HS domains disrupts the kidney glomerular architecture without affecting the glomerular filtration barrier and overall kidney function.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 134-149"},"PeriodicalIF":4.5,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000908/pdfft?md5=086a230b39396661fb6dd8b43ec26ccb&pid=1-s2.0-S0945053X24000908-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472025","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":"MiR-214–3p regulates Piezo1, lysyl oxidases and mitochondrial function in human cardiac fibroblasts","authors":"Christopher J. Trevelyan ,&nbsp;Amanda D.V. MacCannell ,&nbsp;Leander Stewart ,&nbsp;Theodora Tarousa ,&nbsp;Hannah A. Taylor ,&nbsp;Michael Murray ,&nbsp;Sumia A. Bageghni ,&nbsp;Karen E. Hemmings ,&nbsp;Mark J. Drinkhill ,&nbsp;Lee D. Roberts ,&nbsp;Andrew J. Smith ,&nbsp;Karen E. Porter ,&nbsp;Karen A. Forbes ,&nbsp;Neil A. Turner","doi":"10.1016/j.matbio.2024.06.005","DOIUrl":"10.1016/j.matbio.2024.06.005","url":null,"abstract":"<div><p>Cardiac fibroblasts are pivotal regulators of cardiac homeostasis and are essential in the repair of the heart after myocardial infarction (MI), but their function can also become dysregulated, leading to adverse cardiac remodelling involving both fibrosis and hypertrophy. MicroRNAs (miRNAs) are noncoding RNAs that target mRNAs to prevent their translation, with specific miRNAs showing differential expression and regulation in cardiovascular disease. Here, we show that miR-214–3p is enriched in the fibroblast fraction of the murine heart, and its levels are increased with cardiac remodelling associated with heart failure, or in the acute phase after experimental MI. Tandem mass tagging proteomics and in-silico network analyses were used to explore protein targets regulated by miR-214–3p in cultured human cardiac fibroblasts from multiple donors. Overexpression of miR-214–3p by miRNA mimics resulted in decreased expression and activity of the Piezo1 mechanosensitive cation channel, increased expression of the entire lysyl oxidase (LOX) family of collagen cross-linking enzymes, and decreased expression of an array of mitochondrial proteins, including mitofusin-2 (MFN2), resulting in mitochondrial dysfunction, as measured by citrate synthase and Seahorse mitochondrial respiration assays. Collectively, our data suggest that miR-214–3p is an important regulator of cardiac fibroblast phenotypes and functions key to cardiac remodelling, and that this miRNA represents a potential therapeutic target in cardiovascular disease.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 34-46"},"PeriodicalIF":4.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000891/pdfft?md5=dedfa241d4aff0fe56908d1113a212b1&pid=1-s2.0-S0945053X24000891-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460385","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":"Cancer-associated fibroblasts promote proliferation, angiogenesis, metastasis and immunosuppression in gastric cancer","authors":"Peiyuan Li,&nbsp;Huan Zhang,&nbsp;Tao Chen,&nbsp;Yajing Zhou,&nbsp;Jiaoyang Yang,&nbsp;Jin Zhou","doi":"10.1016/j.matbio.2024.06.004","DOIUrl":"10.1016/j.matbio.2024.06.004","url":null,"abstract":"<div><p>Despite advances in surgery, radiotherapy and immunotherapy, the mortality rate for gastric cancer remains one of the highest in the world. A large body of evidence has demonstrated that cancer-associated fibroblasts (CAFs), as core members of the stroma, can secrete cytokines, proteins and exosomes to create a tumour microenvironment that is conducive to cancer cell survival. CAFs can also interact with cancer cells to form a complex signalling network, enabling cancer cells to more easily metastasise to other organs and tissues in the body and develop metastatic foci. In this review, we provide an overview of the CAFs concept and activators. We focus on elucidating their effects on immune cells, intratumoural vasculature, extracellular matrix, as well as cancer cell activity, metastatic power and metabolism, and on enhancing the metastatic ability of cancer cells through activation of JAK/STAT, NF/κB and CXCL12/CXCR4. Various therapeutic agents targeting CAFs are also under development and are expected to improve the prognosis of gastric cancer in combination with existing treatment options.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 59-71"},"PeriodicalIF":4.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X2400088X/pdfft?md5=4f9e9676cb04f16a93eee54c9235018d&pid=1-s2.0-S0945053X2400088X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472024","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":"The fibroblast hormone Endotrophin is a biomarker of mortality in chronic diseases","authors":"Federica Genovese ,&nbsp;Cecilie Bager ,&nbsp;Peder Frederiksen ,&nbsp;Dario Vazquez ,&nbsp;Jannie Marie Bülow Sand ,&nbsp;R Gisli Jenkins ,&nbsp;Toby M. Maher ,&nbsp;Iain D. Stewart ,&nbsp;Philip L. Molyneaux ,&nbsp;William A Fahy ,&nbsp;Louise V. Wain ,&nbsp;Jørgen Vestbo ,&nbsp;Carmel Nanthakumar ,&nbsp;Saher Burhan Shaker ,&nbsp;Nils Hoyer ,&nbsp;Diana Julie Leeming ,&nbsp;Jacob George ,&nbsp;Jonel Trebicka ,&nbsp;Daniel Guldager Kring Rasmussen ,&nbsp;Michael K. Hansen ,&nbsp;Detlef Schuppan","doi":"10.1016/j.matbio.2024.06.003","DOIUrl":"10.1016/j.matbio.2024.06.003","url":null,"abstract":"<div><p>Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases.</p><p>We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PRO<img>C6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PRO<img>C6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available.</p><p>In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (<em>N</em> = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75—2.52) for a 2-fold increase in PRO<img>C6, with some heterogeneity observed between the studies (I²=70 %).</p><p>This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 1-9"},"PeriodicalIF":6.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000854/pdfft?md5=9e4a241d5e9ff9bac7f93d4d7fd3e3a7&pid=1-s2.0-S0945053X24000854-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318750","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":"IGF-II regulates lysyl oxidase propeptide and mediates its effects in part via basic helix-loop-helix E40","authors":"Adegboyega Timothy Adewale,&nbsp;Shailza Sharma,&nbsp;Joe E. Mouawad,&nbsp;Xinh-Xinh Nguyen,&nbsp;Amy D. Bradshaw,&nbsp;Carol Feghali-Bostwick","doi":"10.1016/j.matbio.2024.06.002","DOIUrl":"10.1016/j.matbio.2024.06.002","url":null,"abstract":"<div><p>Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF. We sought to identify downstream regulatory mediators of IGF-II. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than control lung tissues. LOX-PP-mediated changes were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP, were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, BMP1, and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localized to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP, and restored features of ECM deregulation triggered by IGF-II. Our findings indicate that IGF-II, BHLHE40, and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 24-33"},"PeriodicalIF":4.5,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141297184","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":"Molecular and epigenetic ex vivo profiling of testis cancer-associated fibroblasts and their interaction with germ cell tumor cells and macrophages","authors":"Alexa Stephan ,&nbsp;Jan-Henrik Suhrmann ,&nbsp;Margaretha A. Skowron ,&nbsp;Yue Che ,&nbsp;Gereon Poschmann ,&nbsp;Patrick Petzsch ,&nbsp;Catena Kresbach ,&nbsp;Wasco Wruck ,&nbsp;Pailin Pongratanakul ,&nbsp;James Adjaye ,&nbsp;Kai Stühler ,&nbsp;Karl Köhrer ,&nbsp;Ulrich Schüller ,&nbsp;Daniel Nettersheim","doi":"10.1016/j.matbio.2024.06.001","DOIUrl":"10.1016/j.matbio.2024.06.001","url":null,"abstract":"<div><p>Germ cell tumors (GCT) are the most common solid tumors in young men of age 15 - 40. In previous studies, we profiled the interaction of GCT cells with cells of the tumor microenvironment (TM), which showed that especially the 3D interaction of fibroblasts (FB) or macrophages with GCT cells influenced the growth behavior and cisplatin response as well as the transcriptome and secretome of the tumor cells, suggesting that the crosstalk of these cells with GCT cells is crucial for tumor progression and therapy outcome.</p><p>In this study, we shed light on the mechanisms of activation of cancer-associated fibroblasts (CAF) in the GCT setting and their effects on GCT cells lines and the monocyte cell line THP-1. <em>Ex vivo</em> cultures of GCT-derived CAF were established and characterized molecularly and epigenetically by performing DNA methylation arrays, RNA sequencing, and mass spectrometry-based secretome analysis.</p><p>We demonstrated that the activation state of CAF is influenced by their former prevailing tumor environment in which they have resided. Hereby, we postulate that seminoma (SE) and embryonal carcinoma (EC) activate CAF, while teratoma (TER) play only a minor role in CAF formation. In turn, CAF influence proliferation and the expression of cisplatin sensitivity-related factors in GCT cells lines as well as polarization of <em>in vitro</em>-induced macrophages by the identified effector molecules IGFBP1, LGALS3BP, LYVE1, and PTX3.</p><p>Our data suggests that the vital interaction of CAF with GCT cells and with macrophages has a huge influence on shaping the extracellular matrix as well as on recruitment of immune cells to the TM. In conclusion, therapeutically interfering with CAF and / or macrophages in addition to the standard therapy might slow-down progression of GCT and re-shaping of the TM to a tumor-promoting environment.</p><p>Significance: The interaction of CAF with GCT and macrophages considerably influences the microenvironment. Thus, therapeutically interfering with CAF might slow-down progression of GCT and re-shaping of the microenvironment to a tumor-promoting environment.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 10-23"},"PeriodicalIF":6.9,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000775/pdfft?md5=233b8097421e2225d8cf6fc3ee1b782b&pid=1-s2.0-S0945053X24000775-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293904","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":"Ameloblastin and its multifunctionality in amelogenesis: A review","authors":"Natalie C. Kegulian ,&nbsp;Gayathri Visakan ,&nbsp;Rucha Arun Bapat,&nbsp;Janet Moradian-Oldak","doi":"10.1016/j.matbio.2024.05.007","DOIUrl":"10.1016/j.matbio.2024.05.007","url":null,"abstract":"<div><p>Extracellular matrix proteins play crucial roles in the formation of mineralized tissues like bone and teeth via multifunctional mechanisms. In tooth enamel, ameloblastin (Ambn) is one such multifunctional extracellular matrix protein implicated in cell signaling and polarity, cell adhesion to the developing enamel matrix, and stabilization of prismatic enamel morphology. To provide a perspective for Ambn structure and function, we begin this review by describing dental enamel and enamel formation (amelogenesis) followed by a description of enamel extracellular matrix. We then summarize the established domains and motifs in Ambn protein, human <em>amelogenesis imperfecta</em> cases, and genetically engineered mouse models involving mutated or null <em>Ambn.</em> We subsequently delineate <em>in silico, in vitro</em>, and <em>in vivo</em> evidence for the amphipathic helix in Ambn as a proposed cell-matrix adhesive and then more recent <em>in vitro</em> evidence for the multitargeting domain as the basis for dynamic interactions of Ambn with itself, amelogenin, and membranes. The multitargeting domain facilitates tuning between Ambn-membrane interactions and self/co-assembly and supports a likely overall role for Ambn as a matricellular protein. We anticipate that this review will enhance the understanding of multifunctional matrix proteins by consolidating diverse mechanisms through which Ambn contributes to enamel extracellular matrix mineralization.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"131 ","pages":"Pages 62-76"},"PeriodicalIF":6.9,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181124","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":"Sdc4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging mouse spine","authors":"Kimheak Sao ,&nbsp;Makarand V. Risbud","doi":"10.1016/j.matbio.2024.05.006","DOIUrl":"10.1016/j.matbio.2024.05.006","url":null,"abstract":"<div><p>Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of <em>Sdc4</em> global knockout (KO) mice as a function of age. Micro-computed tomography showed that <em>Sdc4</em> deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in <em>Sdc4</em> KO mice. These changes in vertebral bone were likely due to elevated osteoclastic activity. The histological assessment showed subtle phenotypic changes in the intervertebral disc. Imaging-Fourier transform-infrared analyses showed a reduced relative ratio of mature collagen crosslinks in young adult nucleus pulposus (NP) and annulus fibrosus (AF) of KO compared to wildtype discs. Additionally, relative chondroitin sulfate levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, endoplasmic reticulum (ER)-associated misfolded protein processes and ER to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the mouse intervertebral disc.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"131 ","pages":"Pages 46-61"},"PeriodicalIF":6.9,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162775","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":"Collagen XVIII regulates extracellular matrix integrity in the developing nephrons and impacts nephron progenitor cell behavior","authors":"Mia M. Rinta-Jaskari ,&nbsp;Florence Naillat ,&nbsp;Heli J. Ruotsalainen ,&nbsp;Veli-Pekka Ronkainen ,&nbsp;Ritva Heljasvaara ,&nbsp;Saad U. Akram ,&nbsp;Valerio Izzi ,&nbsp;Ilkka Miinalainen ,&nbsp;Seppo J. Vainio ,&nbsp;Taina A. Pihlajaniemi","doi":"10.1016/j.matbio.2024.05.005","DOIUrl":"10.1016/j.matbio.2024.05.005","url":null,"abstract":"<div><p>Renal development is a complex process in which two major processes, tubular branching and nephron development, regulate each other reciprocally. Our previous findings have indicated that collagen XVIII (ColXVIII), an extracellular matrix protein, affects the renal branching morphogenesis. We investigate here the role of ColXVIII in nephron formation and the behavior of nephron progenitor cells (NPCs) using isoform-specific ColXVIII knockout mice. The results show that the short ColXVIII isoform predominates in the early epithelialized nephron structures whereas the two longer isoforms are expressed only in the later phases of glomerular formation. Meanwhile, electron microscopy showed that the ColXVIII mutant embryonic kidneys have ultrastructural defects at least from embryonic day 16.5 onwards. Similar structural defects had previously been observed in adult ColXVIII-deficient mice, indicating a congenital origin. The lack of ColXVIII led to a reduced NPC population in which changes in NPC proliferation and maintenance and in macrophage influx were perceived to play a role. The changes in NPC behavior in turn led to notably reduced overall nephron formation. In conclusion, the results show that ColXVIII has multiple roles in renal development, both in ureteric branching and in NPC behavior.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"131 ","pages":"Pages 30-45"},"PeriodicalIF":6.9,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000660/pdfft?md5=224053ebc87274accced0b682c6584ee&pid=1-s2.0-S0945053X24000660-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093328","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":"Role of amelogenin phosphorylation in regulating dental enamel formation","authors":"Claire M. Gabe ,&nbsp;Ai Thu Bui ,&nbsp;Lyudmila Lukashova ,&nbsp;Kostas Verdelis ,&nbsp;Brent Vasquez ,&nbsp;Elia Beniash ,&nbsp;Henry C. Margolis","doi":"10.1016/j.matbio.2024.05.004","DOIUrl":"10.1016/j.matbio.2024.05.004","url":null,"abstract":"<div><p>Amelogenin (AMELX), the predominant matrix protein in enamel formation, contains a singular phosphorylation site at Serine 16 (S16) that greatly enhances AMELX's capacity to stabilize amorphous calcium phosphate (ACP) and inhibit its transformation to apatitic enamel crystals. To explore the potential role of AMELX phosphorylation in vivo, we developed a knock-in (KI) mouse model in which AMELX phosphorylation is prevented by substituting S16 with Ala (A). As anticipated, AMELX^S16A KI mice displayed a severe phenotype characterized by weak hypoplastic enamel, absence of enamel rods, extensive ectopic calcifications, a greater rate of ACP transformation to apatitic crystals, and progressive cell pathology in enamel-forming cells (ameloblasts). In the present investigation, our focus was on understanding the mechanisms of action of phosphorylated AMELX in amelogenesis. We have hypothesized that the absence of AMELX phosphorylation would result in a loss of controlled mineralization during the secretory stage of amelogenesis, leading to an enhanced rate of enamel mineralization that causes enamel acidification due to excessive proton release. To test these hypotheses, we employed microcomputed tomography (µCT), colorimetric pH assessment, and Fourier Transform Infrared (FTIR) microspectroscopy of apical portions of mandibular incisors from 8-week old wildtype (WT) and KI mice. As hypothesized, µCT analyses demonstrated significantly higher rates of enamel mineral densification in KI mice during the secretory stage compared to the WT. Despite a greater rate of enamel densification, maximal KI enamel thickness increased at a significantly lower rate than that of the WT during the secretory stage of amelogenesis, reaching a thickness in mid-maturation that is approximately half that of the WT. pH assessments revealed a lower pH in secretory enamel in KI compared to WT mice, as hypothesized. FTIR findings further demonstrated that KI enamel is comprised of significantly greater amounts of acid phosphate compared to the WT, consistent with our pH assessments. Furthermore, FTIR microspectroscopy indicated a significantly higher mineral-to-organic ratio in KI enamel, as supported by µCT findings. Collectively, our current findings demonstrate that phosphorylated AMELX plays crucial mechanistic roles in regulating the rate of enamel mineral formation, and in maintaining physico-chemical homeostasis and the enamel growth pattern during early stages of amelogenesis.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"131 ","pages":"Pages 17-29"},"PeriodicalIF":6.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959746","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}