Proteoglycan research最新文献

{"title":"Proteoglycans in Mechanobiology of Tissues and Organs: Normal Functions and Mechanopathology.","authors":"Mary C Farach-Carson, Danielle Wu, Cristiane Miranda França","doi":"10.1002/pgr2.21","DOIUrl":"10.1002/pgr2.21","url":null,"abstract":"<p><p>Proteoglycans (PGs) are a diverse class of glycoconjugates that serve critical functions in normal mechanobiology and mechanopathology. Both the protein cores and attached glycosaminoglycan (GAG) chains function in mechanically-sensitive processes, and loss of either can contribute to development of pathological conditions. PGs function as key components of the extracellular matrix (ECM) where they can serve as mechanosensors in mechanosensitive tissues including bone, cartilage, tendon, blood vessels and soft organs. The mechanical properties of these tissues depend on the presence and function of PGs, which play important roles in tissue elasticity, osmolarity and pressure sensing, and response to physical activity. Tissue responses depend on cell surface mechanoreceptors that include integrins, CD44, voltage sensitive ion channels, transient receptor potential (TRP) and piezo channels. PGs contribute to cell and molecular interplay in wound healing, fibrosis, and cancer, where they transduce the mechanical properties of the ECM and influence the progression of various context-specific conditions and diseases. The PGs that are most important in mechanobiology vary depending on the tissue and its functions and functional needs. Perlecan, for example, is important in the mechanobiology of basement membranes, cardiac and skeletal muscle, while aggrecan plays a primary role in the mechanical properties of cartilage and joints. A variety of techniques have been used to study the mechanobiology of PGs, including atomic force microscopy, mouse knockout models, and <i>in vitro</i> cell culture experiments with 3D organoid models. These studies have helped to elucidate the tissue-specific roles that PGs play in cell-level mechanosensing and tissue mechanics. Overall, the study of PGs in mechanobiology is yielding fundamental new concepts in the molecular basis of mechanosensing that can open the door to the development of new treatments for a host of conditions related to mechanopathology.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"2 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VAR2HP recognizing heparin‐like epitopes in targeted therapy and diagnosis of tumors","authors":"Yingying Xu, Yi Liu, Ruyi Zou, Xunyi Yuan, Lin Wei, Yong Qin, Xu Wang, Yunxue Zhao, Zhenqiu Yang, Wenshuang Wang, Fuchuan Li","doi":"10.1002/pgr2.16","DOIUrl":"https://doi.org/10.1002/pgr2.16","url":null,"abstract":"The synthesis of glycosaminoglycans (GAGs) in vivo occurs with high spatiotemporal specificity, and any aberrant expression of GAGs is closely related to the occurrence of diseases. In terms of tumorigenesis, the abnormally expressed GAGs have become a potential target for the diagnosis and therapy of tumors. As previously reported, VAR2HP, a protein probe that recognizes the unique heparin (Hep)‐like epitopes, interacts with a decasaccharide structure containing at least three HexA2S(1‐4)GlcNS6S disaccharides. Its recognition epitopes are overexpressed in various tumor cells and appear promising as target molecules of multiple tumors. Herein, we found that VAR2HP used as an antineoplastic carrier could promote drug enrichment in tumor sites by targeting the specific Hep‐like epitopes on tumor cells, thereby reducing the damage to normal cells in vitro and in vivo. Moreover, VAR2HP acting on cells alone could inhibit cell proliferation, indicating that VAR2HP as a drug carrier has a dual effect of antitumor activity. Additionally, we observed that VAR2HP significantly stained cancer tissues more strongly than neighboring nonmalignant tissues. The staining was competitively inhibited by added exogenous Hep, indicating that the Hep‐like epitopes recognized by VAR2HP were a potential target molecule in tumor diagnosis. Moreover, the VAR2HP‐bound Hep‐like epitopes were found to be overexpressed in the sera of patients with hepatocellular carcinoma (HCC) but not in normal persons and patients with cirrhosis. Taken together, this study shows that VAR2HP and its heparin‐like epitopes have great potential in targeted therapy of tumors and HCC diagnosis.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"16 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140520843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting glypicans through EGFR and JAK/STAT signaling axes drives breast cancer progression","authors":"Paraskevi Ioannou, Kyriaki Tzaferi, Christos Koutsakis, Z. Piperigkou, Nikos K. Karamanos","doi":"10.1002/pgr2.18","DOIUrl":"https://doi.org/10.1002/pgr2.18","url":null,"abstract":"Extracellular matrix (ECM) and its dynamic remodeling contribute to the progression of breast cancer, the most prevailing cancer type in women. Glypicans (GPCs) function as cell co‐receptors by facilitating the formation of ligand–receptor complexes. An important regulator in the context of breast cancer progression is the JAK/STAT signaling pathway that oversees the expression of genes associated with cancer cell characteristics. Epidermal growth factor receptor (EGFR) is a pivotal player in this process. The aim of this study is to examine the effect of the EGFR and JAK/STAT signaling pathways on GPCs expression in breast cancer cells with different estrogen receptor (ER) status, depicting different breast cancer subtypes. To this end, the ERα‐positive MCF‐7, and the ERβ‐positive MDA‐MB‐231 breast cancer cell lines were evaluated in terms of the impact of downstream inhibition of both pathways on the functional properties as well as the expression of GPCs 1‐6 genes. Notably, the downstream inhibition of both EGFR and JAK/STAT cascades mitigate cell proliferation and migration, while increasing cell adhesion on collagen type I in an ER‐independent manner. However, the inhibition exhibited a cell‐line‐dependent effect on GPC expression, as in MCF‐7 cells GPCs expression is mostly downregulated excepting GPC‐4 and GPC‐5. Conversely, in MDA‐MB‐231 cells, EGFR and JAK/STAT activation is essential for maintaining GPCs at low levels. Additionally, STRING analysis identified the small leucine‐rich PG decorin as a putative link between all GPCs and EGFR. Subsequently, a deeper understanding on the effect of EGFR and JAK/STAT signaling may shed light into the role and interplay between GPCs and decorin in breast cancer progression, thus contributing to novel therapeutic solutions.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140524082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heparanase‐1 and MMPs in Covid‐19 and non‐Covid‐19 pneumonia","authors":"V. Masola, G. Marrone, Carola Condoluci, Marco Franchi, Leonardo Stella, M. Biolato, Luca Miele, Giovanni Gambaro, Claudia Dal Vecchio, M. Onisto","doi":"10.1002/pgr2.14","DOIUrl":"https://doi.org/10.1002/pgr2.14","url":null,"abstract":"Together with the ACE2 protein, heparan sulfate present at the level of the glycocalyx in the lung epithelia is considered a cellular “co‐receptor” for the viral spike protein that allows severe acute respiratory syndrome coronavirus 2 (SARS‐CoV) to infect cells. An increase in the amount and activity of heparanase‐1 (HPSE), the only enzyme capable of degrading the heparan sulfate (HS) chains of the glycocalyx and of the extracellular matrix, has been described in the plasma of patients affected by coronavirus disease 2019 (Covid‐19). Furthermore, the activity of matrix metalloproteases, or MMPs, has been related to matrix degradation, oxidative stress, and inflammation in Covid‐19 patients. In this study, we enrolled 26 Covid‐19 patients and 15 controls with diagnosis of non‐SARS‐CoV‐2‐related pneumonia. We evaluated the expression and activity of HPSE and the expression of MMPs in their serum together with other clinical markers of disease and inflammation. Results proved that HPSE expression and activity serum levels were significantly increased, whereas MMP2 and 9 were decreased in Covid‐19 versus non‐Covid‐19 pneumonia patients. In addition, IL‐6 levels were higher, whereas platelet and white blood cells were lower in Covid‐19 with respect to non‐Covid‐19 pneumonia. Moreover, MMP9 but not HPSE (expression and activity) levels were increased in Covid‐19 pneumonia patients with ongoing lung alteration over time. In summary, the present findings indicate that HPSE and MMPs are differentially regulated in Covid‐19 and non‐Covid‐19 pneumonia.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"78 1-2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140523712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo activities of heparan sulfate differentially modified by NDSTs during development","authors":"E. Nakato, Sarah Baker, A. Kinoshita-Toyoda, Collin Knudsen, Yi‐Si Lu, Masahiko Takemura, Hidenao Toyoda, H. Nakato","doi":"10.1002/pgr2.17","DOIUrl":"https://doi.org/10.1002/pgr2.17","url":null,"abstract":"Heparan sulfate proteoglycans (HSPGs) serve as co‐receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HS N‐deacetylase/N‐sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock‐in (KI) Drosophila strains with the insertion of mouse Ndst1 (mNdst1) or Ndst2 (mNdst2) in the locus of sulfateless (sfl), the only Drosophila NDST. In these KI lines, mNDSTs are expressed from the sfl locus, in the level and patterns identical to the endogenous sfl gene. Thus, phenotypes of Ndst1 KI and Ndst2KI animals reflect the ability of HS structures made by these enzymes to rescue sfl mutation. Remarkably, we found that mNdst1 completely rescued the loss of sfl. mNdst2 showed a limited rescue ability, despite a higher level of HS sulfation compared to HS in mNdst1 KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"76 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140524922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel biomimetic probe for galectin‐3 recognition: Chemical synthesis and structural characterization of a β‐galactose branched sodium hyaluronate","authors":"Sofia Nizzolo, Emiliano Esposito, Ming‐Hong Ni, Laura Bertocchi, Giulio Bianchini, Nadia Freato, Serena Zanzoni, Marco Guerrini, Sabrina Bertini","doi":"10.1002/pgr2.19","DOIUrl":"https://doi.org/10.1002/pgr2.19","url":null,"abstract":"Sodium hyaluronate (HA), a derivative of hyaluronan, is a natural and biocompatible polysaccharide that interacts with cluster of differentiation‐44 receptor to promote fine‐tuning of inflammation, fibrosis, and tissue remodeling. HA has a smaller molecular weight than hyaluronan and is overall more stable being less prone to oxidation. In this study, we report a novel lactose‐functionalized sodium hyaluronate, named HYLACH®. Functionalization with multiple β‐galactose residues facilitates its interaction with galectin‐3, a β‐galactose binding lectin implicated in various pathological processes including inflammation, host defense, and fibrosis, especially critical in idiopathic pulmonary fibrosis (IPF). Our strategy was to modify HA, to varying extents, at carboxyl sites with 1‐amino‐1‐deoxy‐lactitol, in the presence of 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methyl morpholinium chloride in aqueous media. We characterized the chemical structure, molecular weight, and degree of substitution of HYLACH® using NMR spectroscopy and size exclusion chromatography. We further determined several key parameters including its stability toward enzymatic degradation and the binding affinity and conformational changes of galectin‐3 interaction with HYLACH®. Collectively, the generation of a novel functionalized HA with an ability to bind and suppress galectin‐3 function, in combination with safety and biocompatibility, offers the opportunity to test this compound in therapeutic trials of devastating fibrotic diseases such as IPF.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"105 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140515769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chondroitin sulfate proteoglycan promotes APRIL‐induced tumor cell proliferation","authors":"S. Nadanaka, Toshiyasu Koike, Hiroshi Kitagawa","doi":"10.1002/pgr2.15","DOIUrl":"https://doi.org/10.1002/pgr2.15","url":null,"abstract":"A proliferation‐inducing ligand (APRIL), a member of the tumor necrosis factor superfamily, affects the survival and proliferation of tumor cells. Understanding the mechanism of action of APRIL in tumor cells, including intracellular signaling, is important for its potential use in diagnostics and prognosis. It has been shown that APRIL‐induced tumor proliferation requires heparan sulfate (HS) proteoglycans to mediate the binding of APRIL to tumor cells. Here, we show that chondroitin sulfate (CS) proteoglycan mainly contributes to the APRIL‐stimulated proliferation of triple‐negative breast cancer BT‐549 cells. Knockout of chondroitin 4‐O‐sulfotransferase‐1 (C4ST‐1), a key CS biosynthetic enzyme, suppressed APRIL‐induced tumor proliferation, whereas deficiency of exostosin 1 (EXT1), a key HS biosynthetic enzyme, had only weak effects. Molecular interaction analyses using Biacore revealed that although CS did not directly bind to tumor growth through Ca2+ modulator interactor (TACI), it enhanced the binding of APRIL to the APRIL receptor, TACI. The small leucine‐rich proteoglycan, biglycan, plays a pivotal role in tumor growth and progression. Biglycan knockdown inhibited BT‐549 cell proliferation. These results suggest that CS synthesized by C4ST‐1 participates in APRIL signaling and modulates pathological events in tumors.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"9 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139633520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Versican and versikine: The dynamism of the extracellular matrix","authors":"Hideto Watanabe","doi":"10.1002/pgr2.13","DOIUrl":"https://doi.org/10.1002/pgr2.13","url":null,"abstract":"Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan in the extracellular matrix and one of the aggrecan/lectican family. Whereas versican is constitutively expressed and serves as a structural macromolecule in some tissues, it is transiently expressed at high levels when the extracellular matrix dynamically changes. There, versican plays an important role in forming the provisional matrix, which is replaced with the “authentic” extracellular matrix, that is, the matrix as it should be. ADAMTS‐1, 4, 5, 9, 15, and 20 cleave versican core protein and are therefore named versicanases. These proteinases have been believed to play a critical role in versican turnover. A cleaved N‐terminal fragment harbors biological functions, and it is termed “versikine.” This review discusses recent advances in the research on the in vivo function of versican and versikine generated by versicanases.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"134 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139330868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heparanase-A single protein with multiple enzymatic and nonenzymatic functions.","authors":"Israel Vlodavsky, Yasmin Kayal, Maram Hilwi, Soaad Soboh, Ralph D Sanderson, Neta Ilan","doi":"10.1002/pgr2.6","DOIUrl":"10.1002/pgr2.6","url":null,"abstract":"<p><p>Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The enzyme appears to fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, autophagy, HS turnover, and gene transcription. It activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and nonenzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive tumor growth, dissemination, and drug resistance as well as inflammatory responses. The emerging premise is that heparanase expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a valid target for therapy. So far, however, antiheparanase-based therapy has not been implemented in the clinic. Unlike heparanase, heparanase-2 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS-degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity towards HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1 regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper balance between Hpa1 and Hpa2.</p>","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"1 3","pages":"e6"},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10398610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10325441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The functional network of biglycan: A new frontier in tumor progression","authors":"Li Yu, Nako Maishi, Aya Matsuda, Kyoko Hida","doi":"10.1002/pgr2.11","DOIUrl":"https://doi.org/10.1002/pgr2.11","url":null,"abstract":"Abstract Biglycan is a member of the small leucine‐rich proteoglycan family. Dysregulation of biglycan leads to a broad range of clinical consequences, such as osteoclastogenesis, inflammation, cardiovascular disease, and cancer. Biglycan binding to toll‐like receptor (TLR)−2 or TLR‐4 on immune cells lead to infiltration of immune cells to mediate the inflammatory response. Additionally, the extracellular matrix‐secreted soluble biglycan functions as a danger‐associated molecular pattern molecule involved in the induction of inflammation and cancer. High expression of biglycan is demonstrated in tumor endothelial cells (TECs) of various cancers and correlates with metastatic potential and poor clinical outcomes. This comprehensive review addresses the role of biglycan in both tumor cells and tumor stromal cells, especially TECs, in regulating tumor angiogenesis, tumor growth, metastasis, and chemotherapy resistance.","PeriodicalId":74585,"journal":{"name":"Proteoglycan research","volume":"148 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136260470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}