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• W2808538217 abstract "Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage. Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage. Mucopolysaccharidoses (MPSs) are lysosomal storage diseases (LSDs) caused by mutations in genes encoding for lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs).1Neufeld E.F. Muenzer J. The mucopolysaccharidoses.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. Eighth Editon. McGraw-Hill, New York2001: 3421-3452Google Scholar The accumulation of undigested GAGs results in the loss of cellular functions, tissue damage, and organ dysfunctions accounting for MPS clinical manifestations that include brain abnormalities and mental retardation; skeletal, joint, airway, and cardiac defects; and hearing and vision impairment. Affected patients usually die in their second or third decade of life. Depending on the accumulated GAGs, MPSs are classified into seven types (I, II, III, IV, VI, VII, and IX) that are variable in their prevalence, clinical symptoms, and degree of severity.2Clarke L.A. The mucopolysaccharidoses: a success of molecular medicine.Expert Rev. Mol. Med. 2008; 10: e1Crossref PubMed Scopus (113) Google Scholar Currently, therapeutic options for MPSs include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), pharmacological chaperone therapy, gene therapy, and hematopoietic stem cells transplantation (HSCT).3Noh H. Lee J.I. Current and potential therapeutic strategies for mucopolysaccharidoses.J. Clin. Pharm. Ther. 2014; 39: 215-224Crossref PubMed Scopus (82) Google Scholar, 4Hollak C.E. Wijburg F.A. Treatment of lysosomal storage disorders: successes and challenges.J. Inherit. Metab. Dis. 2014; 37: 587-598Crossref PubMed Scopus (63) Google Scholar, 5Parenti G. Andria G. Ballabio A. Lysosomal storage diseases: from pathophysiology to therapy.Annu. Rev. Med. 2015; 66: 471-486Crossref PubMed Scopus (266) Google Scholar, 6Poswar F. Baldo G. Giugliani R. Phase I and II clinical trials for the mucopolysaccharidoses.Expert Opin. Investig. Drugs. 2017; 26: 1331-1340Crossref PubMed Scopus (14) Google Scholar Most of these treatments, showing variable and limited efficacy, are not curative, but they only ameliorate the symptoms of the disease. Thus, despite the recent undeniable advances in treatment outcomes for MPS diseases, many challenges still remain. Indeed, ERT, which is based on the administration of a recombinant enzyme replacing the deficient lysosomal one, is unable to correct the MPS-related neurological defects, due to the inability of recombinant enzymes to cross the blood-brain barrier.7Muenzer J. Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.Mol. Genet. Metab. 2014; 111: 63-72Crossref PubMed Scopus (132) Google Scholar Host immune responses as well as the failure to prevent neurological deterioration limit the utility of HSCT therapy for MPSs.8Lutzko C. Kruth S. Abrams-Ogg A.C. Lau K. Li L. Clark B.R. Ruedy C. Nanji S. Foster R. Kohn D. et al.Genetically corrected autologous stem cells engraft, but host immune responses limit their utility in canine alpha-L-iduronidase deficiency.Blood. 1999; 93: 1895-1905PubMed Google Scholar, 9Welling L. Marchal J.P. van Hasselt P. van der Ploeg A.T. Wijburg F.A. Boelens J.J. Early umbilical cord blood-derived stem cell transplantation does not prevent neurological deterioration in mucopolysaccharidosis type III.JIMD Rep. 2015; 18: 63-68Crossref PubMed Scopus (37) Google Scholar Despite improvements, the use of viral vectors in gene therapy is still in development, and it is in clinical trial for some MPS subtypes.6Poswar F. Baldo G. Giugliani R. Phase I and II clinical trials for the mucopolysaccharidoses.Expert Opin. Investig. Drugs. 2017; 26: 1331-1340Crossref PubMed Scopus (14) Google Scholar, 10Shull R. Lu X. Dubé I. Lutzko C. Kruth S. Abrams-Ogg A. Kiem H.P. Goehle S. Schuening F. Millan C. Carter R. Humoral immune response limits gene therapy in canine MPS I.Blood. 1996; 88: 377-379Crossref PubMed Google Scholar, 11Ferla R. Alliegro M. Marteau J.B. Dell’Anno M. Nusco E. Pouillot S. Galimberti S. Valsecchi M.G. Zuliani V. Auricchio A. Non-clinical safety and efficacy of an AAV2/8 vector administered intravenously for treatment of Mucopolysaccharidosis type VI.Mol. Ther. Methods Clin. Dev. 2017; 6: 143-158Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 12Sawamoto K. Chen H.H. Alméciga-Díaz C.J. Mason R.W. Tomatsu S. Gene therapy for Mucopolysaccharidoses.Mol. Genet. Metab. 2018; 123: 59-68Crossref PubMed Scopus (40) Google Scholar, 13Tardieu M. Zérah M. Gougeon M.L. Ausseil J. de Bournonville S. Husson B. Zafeiriou D. Parenti G. Bourget P. Poirier B. et al.Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial.Lancet Neurol. 2017; 16: 712-720Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 14Tardieu M. Zérah M. Husson B. de Bournonville S. Deiva K. Adamsbaum C. Vincent F. Hocquemiller M. Broissand C. Furlan V. et al.Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial.Hum. Gene Ther. 2014; 25: 506-516Crossref PubMed Scopus (183) Google Scholar Due to the limits of these therapeutic strategies, research in progress is still focused on a better understanding of MPS physiopathology and development of more advanced therapeutic approaches. Glycosaminoglycans are linear, negatively charged polysaccharides with molecular weights of about 10–100 kDa. There are two main types of GAGs: non-sulfated, which include hyaluronic acid (HA), and sulfated, which include chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparin, and heparan sulfate (HS).15Jackson R.L. Busch S.J. Cardin A.D. Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes.Physiol. Rev. 1991; 71: 481-539Crossref PubMed Scopus (961) Google Scholar With the exception of HA, all GAGs are covalently attached to a core protein, forming the so-called proteoglycans that are abundantly found at the cell surface and in the extracellular matrix.16Iozzo R.V. Schaefer L. Proteoglycan form and function: A comprehensive nomenclature of proteoglycans.Matrix Biol. 2015; 42: 11-55Crossref PubMed Scopus (683) Google Scholar In particular, HS proteoglycans (HSPGs), either associated with the plasma membrane or localized in the extracellular matrix, modulate the activity of growth factors (GFs), such as fibroblast GF (FGF), vascular endothelial GF (VEGF), hepatocyte GF (HGF), and platelet-derived GF (PDGF), allowing their presentation to the cognate receptors in a biologically favorable form.17Matsuo I. Kimura-Yoshida C. Extracellular modulation of Fibroblast Growth Factor signaling through heparan sulfate proteoglycans in mammalian development.Curr. Opin. Genet. Dev. 2013; 23: 399-407Crossref PubMed Scopus (72) Google Scholar, 18Billings P.C. Pacifici M. Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries.Connect. Tissue Res. 2015; 56: 272-280Crossref PubMed Scopus (103) Google Scholar, 19Kim S.H. Turnbull J. Guimond S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor.J. Endocrinol. 2011; 209: 139-151Crossref PubMed Scopus (802) Google Scholar, 20Kresse H. Schönherr E. Proteoglycans of the extracellular matrix and growth control.J. Cell. Physiol. 2001; 189: 266-274Crossref PubMed Scopus (342) Google Scholar Another fundamental role of HSPGs is their contribution to the generation and long-range maintenance of morphogen gradients during embryogenesis, postnatal development, and regenerative processes.21Lin X. Functions of heparan sulfate proteoglycans in cell signaling during development.Development. 2004; 131: 6009-6021Crossref PubMed Scopus (528) Google Scholar, 22Poulain F.E. Yost H.J. Heparan sulfate proteoglycans: a sugar code for vertebrate development?.Development. 2015; 142: 3456-3467Crossref PubMed Scopus (100) Google Scholar, 23Hufnagel L. Kreuger J. Cohen S.M. Shraiman B.I. On the role of glypicans in the process of morphogen gradient formation.Dev. Biol. 2006; 300: 512-522Crossref PubMed Scopus (47) Google Scholar, 24Chung H. Multhaupt H.A. Oh E.S. Couchman J.R. Minireview: Syndecans and their crucial roles during tissue regeneration.FEBS Lett. 2016; 590: 2408-2417Crossref PubMed Scopus (40) Google Scholar, 25Patel V.N. Pineda D.L. Hoffman M.P. The function of heparan sulfate during branching morphogenesis.Matrix Biol. 2017; 57-58: 311-323Crossref PubMed Scopus (39) Google Scholar Furthermore, HSPGs’ interaction with adhesion molecules, receptor tyrosine kinases (RTKs), and Toll-like receptors accounts for their crucial role in regulating cell adhesion and migration, proliferation, innate immunity, angiogenesis, apoptosis, and autophagy.15Jackson R.L. Busch S.J. Cardin A.D. Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes.Physiol. Rev. 1991; 71: 481-539Crossref PubMed Scopus (961) Google Scholar, 16Iozzo R.V. Schaefer L. Proteoglycan form and function: A comprehensive nomenclature of proteoglycans.Matrix Biol. 2015; 42: 11-55Crossref PubMed Scopus (683) Google Scholar, 17Matsuo I. Kimura-Yoshida C. Extracellular modulation of Fibroblast Growth Factor signaling through heparan sulfate proteoglycans in mammalian development.Curr. Opin. Genet. Dev. 2013; 23: 399-407Crossref PubMed Scopus (72) Google Scholar, 18Billings P.C. Pacifici M. Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries.Connect. Tissue Res. 2015; 56: 272-280Crossref PubMed Scopus (103) Google Scholar, 19Kim S.H. Turnbull J. Guimond S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor.J. Endocrinol. 2011; 209: 139-151Crossref PubMed Scopus (802) Google Scholar, 20Kresse H. Schönherr E. Proteoglycans of the extracellular matrix and growth control.J. Cell. Physiol. 2001; 189: 266-274Crossref PubMed Scopus (342) Google Scholar, 26Gandhi N.S. Mancera R.L. The structure of glycosaminoglycans and their interactions with proteins.Chem. Biol. Drug Des. 2008; 72: 455-482Crossref PubMed Scopus (737) Google Scholar Based on the functional relation between HSPGs and GFs, we developed an innovative approach for the treatment of MPS diseases, hereafter called substrate-masking technology, which uses a specific molecule with high binding affinity for the accumulated substrates (i.e., HS and/or DS). This technique enables us to restore the physiological equilibrium between morphogens or GFs, receptors, and HSPGs, allowing their proper interactions on the cell membrane and, in turn, activating downstream signaling. In particular, in this study we explored the potential therapeutic application of the hepatocyte GF/scatter factor (HGF/SF) natural spliced variant NK1,27Cioce V. Csaky K.G. Chan A.M. Bottaro D.P. Taylor W.G. Jensen R. Aaronson S.A. Rubin J.S. Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF/scatter factor variant with partial agonist/antagonist activity.J. Biol. Chem. 1996; 271: 13110-13115Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar which binds HS and DS with the same high affinity.28Deakin J.A. Blaum B.S. Gallagher J.T. Uhrín D. Lyon M. The binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns.J. Biol. Chem. 2009; 284: 6311-6321Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar We evaluated the capability of NK1 to reduce HS content and consequent lysosomal abnormalities in fibroblasts from MPS I and MPS IIIB patients. Furthermore, we analyzed whether NK1 is able to modulate FGF-signaling activity in MPS I and IIIB primary fibroblasts. Our results provide the basis for the development of a potential strategy to restore signaling pathways disrupted in MPS diseases. The autosomal recessive disorder MPS IIIB, caused by mutations in the gene encoding for the α-N-acetylglucosaminidase (NAGLU) enzyme, is one of the four MPS III (Sanfilippo syndrome) subtypes that are caused by the deficiency of lysosomal enzymes exclusively involved in the degradation of HS.1Neufeld E.F. Muenzer J. The mucopolysaccharidoses.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. Eighth Editon. McGraw-Hill, New York2001: 3421-3452Google Scholar Current treatments for MPS III patients are limited to the clinical management of neurological symptoms.29Fedele A.O. Sanfilippo syndrome: causes, consequences, and treatments.Appl. Clin. Genet. 2015; 8: 269-281Crossref PubMed Scopus (66) Google Scholar, 30Ghosh A. Shapiro E. Rust S. Delaney K. Parker S. Shaywitz A.J. Morte A. Bubb G. Cleary M. Bo T. et al.Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III.Orphanet J. Rare Dis. 2017; 12: 117Crossref PubMed Scopus (20) Google Scholar The first step for testing the efficacy of the substrate-masking technology was to investigate the ability of NK1 to reduce the quantity of accumulated GAGs in vitro, by evaluating 3H-glucosamine content into MPS IIIB primary fibroblasts. GAG chains are composed of disaccharide-repeating units containing a uronic acid (D-glucuronic acid or L-iduronic acid) or a galactose and an amino sugar (D-galactosamine or D-glucosamine). While CS and DS contain galactosamine, heparin and HS contain glucosamine (GlcN), which is incorporated into GAGs after its conversion into glucosamine-6-phosphate (GlcN-6-P), N-acetyl-glucosamine-6-P (GlcNAc-6-P), GlcNAc-1-P, and UDP-alpha-GlcNAc.26Gandhi N.S. Mancera R.L. The structure of glycosaminoglycans and their interactions with proteins.Chem. Biol. Drug Des. 2008; 72: 455-482Crossref PubMed Scopus (737) Google Scholar Since HS is the only GAG accumulated in the MPS IIIB, 3H-glucosamine levels represent a measure of the content of this specific GAG in primary fibroblasts from affected patients. MPS IIIB fibroblasts, grown to 80% confluence in the presence of 3H-glucosamine, were incubated with increasing concentrations of NK1 for 48 hr, and the incorporated radionuclides were measured. A statistically significant reduction of 3H-glucosamine content was observed at all NK1 tested doses as compared to untreated MPS IIIB fibroblasts. The effect of NK1 resulted in being dose dependent; however, at the highest concentration of NK1 (10−6 M), the reduction of 3H-glucosamine content was up to 50% compared to untreated MPS IIIB fibroblasts (Figure 1A). At this concentration, NK1 neither interfered with cell growth and viability nor caused gross changes in cell morphology. Therefore, this dose was chosen for the time course study, in which 3H-glucosamine content was measured over a time interval ranging from 24 to 48 hr. In this set of experiments, the effect of NK1 in reducing 3H-glucosamine content into GAGs was already detectable after 24 hr, and it increased over time (Figure 1B). The major effects were detected at the dose of 10−6 M of NK1 after 48-hr treatment of the MPS IIIB fibroblasts; thus, we selected this dose and incubation time for further experiments. Since NK1 binds with the same affinity both HS and DS,28Deakin J.A. Blaum B.S. Gallagher J.T. Uhrín D. Lyon M. The binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns.J. Biol. Chem. 2009; 284: 6311-6321Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar we also evaluated, by the 3H-glucosamine assay, the ability of NK1 to reduce GAG content in primary fibroblasts from MPS I, II, IIIA, and IVA patients. The results obtained showed a significant reduction of 3H-glucosamine content in NK1-treated fibroblasts from patients affected by MPS I, II, and IIIA (Figure 1C), where the accumulated products are, respectively, HS and DS for MPS I and II and HS for MPS IIIA. Conversely, NK1 treatment of fibroblasts from patients affected by MPS IVA, in which the accumulated substrates are KS and CS, did not show any effect (Figure 1C), consistent with the fact that NK1 does not bind KS and CS. Furthermore, the effect of NK1 on GAG storage levels after 48 hr of treatment was also measured by the Alcian blue method. This is a quantitative dye-binding assay commonly used for the in vitro analysis of sulfated GAGs,31Moskot M. Jakóbkiewicz-Banecka J. Kloska A. Smolińska E. Mozolewski P. Malinowska M. Rychłowski M. Banecki B. Węgrzyn G. Gabig-Cimińska M. Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids.Sci. Rep. 2015; 5: 9378Crossref PubMed Scopus (43) Google Scholar, 32Björnsson S. Simultaneous preparation and quantitation of proteoglycans by precipitation with alcian blue.Anal. Biochem. 1993; 210: 282-291Crossref PubMed Scopus (237) Google Scholar based on the specific interaction between sulfated GAG polymers and the tetravalent cationic dye Alcian blue. The assay is performed at a low pH in order to neutralize all the carboxylic and phosphoric acid groups and at a high ionic strength to eliminate ionic interactions other than those between Alcian blue and sulfated GAGs. Indeed, hyaluronan, a non-sulfated GAG, does not react in this assay. As a result of our investigation, we found a significant decrease of GAG levels in MPS I and MPS IIIB fibroblasts treated with 10−6 M NK1 for 48 hr as compared to untreated fibroblasts (Figure 1D). Moreover, in order to evaluate if HS-binding proteins33Dreyfuss J.L. Regatieri C.V. Jarrouge T.R. Cavalheiro R.P. Sampaio L.O. Nader H.B. Heparan sulfate proteoglycans: structure, protein interactions and cell signaling.An. Acad. Bras. Cienc. 2009; 81: 409-429Crossref PubMed Scopus (173) Google Scholar, 34Heremans A. De Cock B. Cassiman J.J. Van den Berghe H. David G. The core protein of the matrix-associated heparan sulfate proteoglycan binds to fibronectin.J. Biol. Chem. 1990; 265: 8716-8724Abstract Full Text PDF PubMed Google Scholar other than NK1 are able to reduce accumulated HS in MPS fibroblasts, we tested the capability of fibronectin to reduce GAG content in MPS IIIB fibroblasts. These cells, grown to 80% confluence in the presence of 3H-glucosamine, were incubated for 48 hr with fibronectin at the same concentration of NK1, and the incorporated radionuclides were measured. The treatment with 10−6 M fibronectin resulted in a significant increase of 3H-glucosamine content into GAGs in MPS IIIB fibroblasts as compared to untreated fibroblasts (Figure S1A). These results demonstrate the efficacy and specificity of NK1 treatment in reducing GAG storage in the MPS subtypes characterized by an abnormal accumulation of HS and/or DS. In MPSs, the abnormal accumulation of undigested HS into lysosomes results in the enlargement of these organelles that start to occupy almost the whole cytoplasm.35Mizumoto S. Ikegawa S. Sugahara K. Human genetic disorders caused by mutations in genes encoding biosynthetic enzymes for sulfated glycosaminoglycans.J. Biol. Chem. 2013; 288: 10953-10961Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar To test whether NK1 was also able to reduce the lysosomal defects in MPS diseases, we incubated MPS I and MPS IIIB fibroblasts with 10−6 M NK1 for 48 hr, and we labeled lysosomes using LysoTraker. Quantitative confocal microscopy showed that the fluorescence intensity of the lysosomes was significantly reduced in NK1-treated fibroblasts compared to untreated ones (Figure 2A). We also labeled treated and untreated fibroblasts from MPS I and IIIB patients with the specific lysosomal-associated membrane protein 1 (LAMP1)36Carlsson S.R. Fukuda M. The polylactosaminoglycans of human lysosomal membrane glycoproteins lamp-1 and lamp-2. Localization on the peptide backbones.J. Biol. Chem. 1990; 265: 20488-20495Abstract Full Text PDF PubMed Google Scholar in order to evaluate the reduction of the lysosomal storage. Figure 2B shows prominent LAMP1 staining in untreated MPS I and MPS IIIB fibroblasts; upon treatment with 10−6 M NK1 for 48 hr, LAMP1 staining was significantly reduced. This observation was confirmed by western blotting analysis for LAMP1 in cell lysates from NK1-treated MPS I and MPS IIIB fibroblasts and untreated ones. Indeed, a reduction of LAMP1 protein levels was detected in both MPS I and MPS IIIB fibroblasts treated with NK1 as compared to untreated fibroblasts (Figure S1B). Overall, these results demonstrate that cell treatment with NK1 results in a significant reduction of the lysosomal defects in MPS I and MPS IIIB fibroblasts. To verify whether NK1 was able to indirectly modulate FGF signaling by binding the extracellular HS, we performed a titration of the fibroblast GF receptor (FGFR) activation by stimulating starved MPS I and MPS IIIB fibroblasts with increasing doses of the human basic FGF (FGF2), both in the absence and in the presence of 10−6 M NK1. In particular, since activation of FGFR induces a variety of intracellular signaling cascades, including the MAPK/ERK pathway,37Wang Z. Wang Y. Ye J. Lu X. Cheng Y. Xiang L. Chen L. Feng W. Shi H. Yu X. et al.bFGF attenuates endoplasmic reticulum stress and mitochondrial injury on myocardial ischaemia/reperfusion via activation of PI3K/Akt/ERK1/2 pathway.J. Cell. Mol. Med. 2015; 19: 595-607Crossref PubMed Scopus (78) Google Scholar, 38Chua C.C. Rahimi N. Forsten-Williams K. Nugent M.A. Heparan sulfate proteoglycans function as receptors for fibroblast growth factor-2 activation of extracellular signal-regulated kinases 1 and 2.Circ. Res. 2004; 94: 316-323Crossref PubMed Scopus (83) Google Scholar we evaluated by western blotting analysis the phosphorylation levels of ERK1/2 in untreated and NK1-treated fibroblasts from MPS I and III affected patients. The results obtained showed that FGF2 at the concentration of 10−12 M (Figure 3, lane 2, upper and lower blots) was unable to trigger ERK1/2 phosphorylation, whereas, in the presence of NK1, the same concentration of FGF2 promoted a significant phosphorylation of ERK1/2 (Figure 3, lane 5, upper and lower blots). These data suggest that the substrate-masking action of NK1 prevents the trapping of FGF2 by the excess of extracellular HS, thus increasing its availability and making FGF2 able to activate the FGFR-signaling cascade. On the other hand, a reduction of ERK1/2 phosphorylation levels was observed at higher FGF2 concentrations (10−11 M and 10−10 M) in the presence of NK1 (Figure 3, lanes 6 and 7, upper and lower blots) as compared to un-pretreated cells (Figure 3, lanes 3 and 4, upper and lower blots). Indeed, in this case, the substrate-masking activity of NK1 limits the availability of HSPG-binding sites for FGF2 with a consequent decrease of ERK1/2 phosphorylation. Thus, even if FGF2 concentration would increase, in the presence of 10−6 M NK1, the effect on ERK1/2 phosphorylation will be always the same due to the same residual availability of HSPG. The administration of NK1 alone to the cells in the absence of FGF2 had no effect on ERK1/2 phosphorylation (Figure 3, lane 8, upper and lower blots), thus ruling out the potential ERK1/2 activation by NK1 itself.39Pavone L.M. Cattaneo F. Rea S. De Pasquale V. Spina A. Sauchelli E. Mastellone V. Ammendola R. Intracellular signaling cascades triggered by the NK1 fragment of hepatocyte growth factor in human prostate epithelial cell line PNT1A.Cell. Signal. 2011; 23: 1961-1971Crossref PubMed Scopus (20) Google Scholar Overall, these data show that NK1 treatment in MPS fibroblasts is able to modulate FGF2-signaling activity by masking the excess of accumulated extracellular HS (Figure 4). Our study describes an innovative potential strategy to rescue cell-signaling pathway alterations that contribute to MPS pathology.40Costa R. Urbani A. Salvalaio M. Bellesso S. Cieri D. Zancan I. Filocamo M. Bonaldo P. Szabò I. Tomanin R. Moro E. Perturbations in cell signaling elicit early cardiac defects in mucopolysaccharidosis type II.Hum. Mol. Genet. 2017; 26: 1643-1655Crossref PubMed Scopus (25) Google Scholar, 41Kingma S.D.K. Wagemans T. IJlst L. Bronckers A.L.J.J. van Kuppevelt T.H. Everts V. Wijburg F.A. van Vlies N. Altered interaction and distribution of glycosaminoglycans and growth factors in mucopolysaccharidosis type I bone disease.Bone. 2016; 88: 92-100Crossref PubMed Scopus (19) Google Scholar This strategy is based on the high binding affinity of the HGF/SF spliced variant NK1 for HS,28Deakin J.A. Blaum B.S. Gallagher J.T. Uhrín D. Lyon M. The binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns.J. Biol. Chem. 2009; 284: 6311-6321Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar whose accumulation in cells and tissues is the main cause of MPS disease. The mesenchymal factor HGF/SF provides growth, motility, and morphogenic stimuli to epithelial, endothelial, and neural cells via exclusive activation of the tyrosine kinase receptor MET.42Trusolino L. Bertotti A. Comoglio P.M. MET signalling: principles and functions in development, organ regeneration and cancer.Nat. Rev. Mol. Cell Biol. 2010; 11: 834-848Crossref PubMed Scopus (915) Google Scholar Although the affinity of HGF/SF for MET is very high,43Mark M.R. Lokker N.A. Zioncheck T.F. Luis E.A. Godowski P.J. Expression and characterization of hepatocyte growth factor receptor-IgG fusion proteins. Effects of mutations in the potential proteolytic cleavage site on processing and ligand binding.J. Biol. Chem. 1992; 267: 26166-26171Abstract Full Text PDF PubMed Google Scholar subsequent activation of the receptor leading to sustained and effective downstream signaling is highly dependent upon GAG co-factors.44Xu D. Esko J.D. Demystifying heparan sulfate-protein interactions.Annu. Rev. Biochem. 2014; 83: 129-157Crossref PubMed Scopus (484) Google Scholar, 45Deakin J.A. Lyon M. Differential regulation of hepatocyte growth factor/scatter factor by cell surface proteoglycans and free glycosaminoglycan chains.J. Cell Sci. 1999; 112: 1999-2009Crossref PubMed Google Scholar, 46Lyon M. Deakin J.A. Gallagher J.T. The mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor.J. Biol. Chem. 2002; 277: 1040-1046Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 47Rubin J.S. Day R.M. Breckenridge D. Atabey N. Taylor W.G. 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• W2808538217 title "Targeting Heparan Sulfate Proteoglycans as a Novel Therapeutic Strategy for Mucopolysaccharidoses" @default.
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