Jean-Pierre Caruelle

Université Paris-Est Créteil Val de Marne - Université Paris 12, Créteil, Île-de-France, France

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Publications (16)34.74 Total impact

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    ABSTRACT: Abstract Heparin and heparan sulfate proteoglycans (HSPGs) stabilize FGFs which belong to heparin-binding growth factors (HBGFs) on active conformation. They also strongly potentiate their mitogenic activity on many cell types, and protect them against thermal denaturation and enzymatic degradation. In the present work we have tested two heparin-like substances named mesoglycan and sulodexide obtained from bovine intestinal mucosal extracts. These products are used as heparin, in various of therapeutic fields such as atherosclerosis or antithrombotic therapy. The compositions of mesoglycan and sulodexide are partially known and include chondroitin, dermatan and heparan sulfate. We have shown that mesoglycan and sulodexide potentiated the mitogenic activity of FGF1 and FGF2. The magnitude of this effect was identical with that of heparin used as a control substance but at double concentration. Mesoglycan and sulodexide also exerted stabilizing and protective effects on FGFs for heat denaturation and enzymatic degradation. The suppression of the protective properties after heparinase treatment of mesoglycan and sulodexide indirectly demonstrated the presence of heparan sulfate which was shown to represent about 60% of the commercial products.
    Growth Factors 07/2009; 11(4):291-300. · 2.20 Impact Factor
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    ABSTRACT: OTR4120, which belongs to a family of heparan sulfate-mimetic polymers, promotes tissue repair when injected locally in doses of a few micrograms. As OTR4120 is a sulfated polysaccharide, we investigated its possible role on the coagulation cascade. We used both in vitro and in vivo assays. Increases in clotting times (thrombin time, prothrombin time, and activated partial thromboplastin time) occurred with OTR4120 in doses at least 10 times lower than heparin. OTR4120 dose-dependently inhibited the biological activity of thrombin and bound thrombin with an affinity of 14 +/- 2 nM. SDS-PAGE showed that OTR4120 induced the formation of covalently linked complexes between antithrombin III or heparin cofactor II and thrombin. OTR4120 induced anticoagulant effects, and antithrombin activity was greatest 90 min after intraperitoneal injection. No bleeding or significant platelet count changes occurred with doses smaller than 55 mg/kg. Interestingly, orally administered OTR4120 crossed the gastrointestinal barrier and, in a dose of 70 mg/kg, induced significant ex vivo antithrombotic activity in the bloodstream.
    Journal of Biomedical Materials Research Part A 01/2008; 83(4):1024-31. · 2.83 Impact Factor
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    ABSTRACT: A family of biopolymers engineered to protect and stabilize heparin binding growth factors (HBGFs) show remarkable properties as wound healing agents in several in vivo tissue repair models to the extend that damaged tissues would recover almost its initial aspect and properties. These polymers where named RGTA for regenerating agents and proposed to act in vivo by enhancing the bioavailability of HBGFs at the site of the injury. To provide support for this hypothesis, we studied interaction of RGTA with FGF-2, taken as the paradigm of HBGFs, and its high- and low-affinity receptors as well as its ability to inhibit heparanase activity. We show that RGTA is comparable to heparin as it favors FGF-2 binding to FGFR-1 and FGF-2 dimerization and potentiates FGF-2-induced mitogenic activity. Furthermore, we show that RGTA inhibits the release of FGF-2 from its extracellular matrix storage sites by heparanase. Our data provide new evidence to support that RGTA may act in vivo both by enhancing HBGF activity and preserving HBGF availability by protecting the matrix low affinity heparan sulfates from rapid heparanase degradation.
    Journal of Biomedical Materials Research Part A 10/2006; 78(4):792-7. · 2.83 Impact Factor
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    ABSTRACT: In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia (Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. (1999) FASEB J. 13, 761-766). In the present study, we showed that the RGTA OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dose-dependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 (VEGF165). OTR4120 showed high affinity binding to VEGF165 (Kd = 2.2 nm), as compared with heparin (Kd = 15 nm), and potentiated the affinity of VEGF165 for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF165-induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF165-induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF165-induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.
    Journal of Biological Chemistry 10/2005; 280(38):32792-800. · 4.65 Impact Factor
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    ABSTRACT: Reproducible and nondegradative preparation of sulfated molecules exhibiting diverse biological properties requires caring out sulfation reactions under ready controlled mild conditions. Although, to date, sulfur trioxide is the most used sulfation agent, its highly acid character has brought its use in association with different nitrogen bases as sulfur trioxide−nitrogen base complexes and/or by introduction of basic solvents as pyridine. We have applied sulfur trioxide and other sulfation agents including protocols for the synthesis of biologically active sulfated polysaccharides and demonstrated that these agents provoke cleavage of glycosidic bonds and other acid labile functions as amides, esters and even ethers. These facts prompted us to develop new reaction conditions for a general and nondestructive sulfation protocol. Our approach consists of the introduction of 2-methyl-2-butene as an acid scavenger of neutral character. Application of the method leads to an efficient, reproducible, and controlled synthesis of acid labile dextran derivatives well-known to be active in tissue repair and recently proposed for example as a new therapeutic agent for prion diseases. A novel 1H NMR structural analysis of this kind of macromolecules is presented. This method offers a new advance for more efficient synthesis of biologically active sulfated macromolecules.
    Macromolecules. 04/2005; 38(11).
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    ABSTRACT: Crucial events in myogenesis rely on the highly regulated spatiotemporal distribution of cell surface heparan sulfate proteoglycans to which are associated growth factors, thus creating a specific microenvironment around muscle cells. Most growth factors involved in control of myoblast growth and differentiation are stored in the extracellular matrix through interaction with specific sequences of glycosaminoglycan oligosaccharides, mainly heparan sulfate (HS). Different HS subspecies revealed by specific antibodies, have been shown to provide spatiotemporal regulation during muscle development. We have previously shown that glycosaminoglycan (GAG) mimetics called RGTA (ReGeneraTing Agent), stimulate muscle precursor cell growth and differentiation. These data suggest an important role of GAGs during myogenesis; however, little is yet known about the different species of GAGs synthesized during myogenesis and their metabolic regulation. We therefore quantified GAGs during myogenesis of C2.7 cells and show that the composition of GAG species was modified during myogenic differentiation. In particular, HS levels were increased during this process. In addition, the GAG mimetic RGTA, which stimulated both growth and differentiation of C2.7 cells, increased the total amount of GAG produced by these cells without significantly altering their rate of sulfation. RGTA treatment further enhanced HS levels and changed its sub-species composition. Although mRNA levels of the enzymes involved in HS biosynthesis were almost unchanged during myogenic differentiation, heparanase mRNA levels decreased. RGTA did not markedly alter these levels. Here we show that the effects of RGTA on myoblast growth and differentiation are in part mediated through an alteration of GAG species and provide an important insight into the role of these molecules in normal or pathologic myogenic processes.
    Journal of Cell Science 02/2005; 118(Pt 1):253-64. · 5.88 Impact Factor
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    ABSTRACT: Oral mucositis is a common, treatment-limiting, and costly side effect of cancer treatments whose biological underpinnings remain poorly understood. In this study, mucositis induced in hamsters by 5-fluorouracil (5-FU) was observed after cheek-pouch scarifications, with and without administration of RGTA (RG1503), a polymer engineered to mimic the protective effects of heparan sulfate. RG1503 had no effects on 5-FU-induced decreases in body weight, blood cell counts, or cheek-pouch and jejunum epithelium proliferation rates, suggesting absence of interference with the cytotoxic effects of 5-FU. Extensive mucositis occurred in all of the untreated animals, and consisted of severe damage to cheek pouch tissues (epithelium, underlying connective tissue, and muscle bundles). Only half of the RG1503-treated animals had mucositis, over a mean area 70% smaller than in the untreated animals. Basement membranes were almost completely destroyed in the untreated group but was preserved in the RG1503 group. RG1503 blunted or abolished the following 5-FU-induced effects: increases in matrix metalloproteinase (MMP)-2, MMP-9, and plasmin, and decreases in tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These data indicate that mucositis lesions are related to massive release of proteolytic enzymes and are improved by RG1503 treatment, this effect being ascribable in part to restoration of the MMP-TIMP balance. RG1503 given with cancer treatment might protect patients from mucositis.
    American Journal Of Pathology 03/2004; 164(2):739-46. · 4.60 Impact Factor
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    American Journal of Pathology - AMER J PATHOL. 01/2004; 164(2):739-746.
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    ABSTRACT: The regenerating activities of chemically modified anionic bacterial polysaccharides by O-sulfonation were investigated using a in vivo model of rat injured muscle regeneration. Glucuronan (GA), a linear homopolysaccharide of -->4)-beta-D-GlcpA-(1--> residues partially acetylated at the C-3 and/or the C-2 position, and glucoglucuronan (GGA), a linear heteropolysaccharide of -->3)-beta-D-GlcpA-(1-->4)-beta-D-Glcp-(1--> residues were sulfated. SO3-DMF sulfatation complex provided polysaccharides with different sulfur contents, however, a depolymerization occurred because we did not use large excess of pyridine to obtain pure modified polysaccharides. A regenerating activity on injured extensor digitorum longus (EDL) muscles on rats was obtained with these two sulfated anionic polymers. The position of sulfate groups on glucoglucuronan (primary or secondary alcohol) seems to have no influence on the biological activity by opposition to the degree of sulfatation both for the glucuronans and the glucoglucuronans. The yield of acetate groups in the glucuronan polymer modulated the specific activity.
    Biomacromolecules 01/2004; 5(2):445-52. · 5.37 Impact Factor
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    ABSTRACT: This article describes a simple and selective procedure used for direct measurement of sulfated glycosaminoglycans (GAGs) in biological samples and its application to the determination of GAGs during tissue regeneration and myogenic differentiation. We describe a modified procedure of previous GAG assays that has improved specificity, reproducibility, and sensitivity. The assay is based on the ability of sulfated GAGs to bind the cationic dye 1,9-dimethylmethylene blue. We describe conditions that allow isolation of the GAG-dye complex. This complex was dissociated; the optical density measurement of the dissociated dye permitted quantification of GAGs in biological samples. Applied to the study of myogenic cell differentiation in vitro, muscle repair, and skin ulceration, this method revealed significant modifications in the patterns of expression of different sulfated GAGs in these tissues. In particular, application of the method after nitrous acid treatment revealed that heparan sulfate and chondroitin sulfate ratio changed during muscle regeneration process.
    Glycobiology 10/2003; 13(9):647-53. · 3.54 Impact Factor
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    ABSTRACT: A family of heparan-like polymers, RGTAs, was shown to promote repair of various tissues. Like heparin and heparan-sulfates, RGTAs potentiate in vitro the biological activities of heparin-binding growth factors (HBGFs) and protect them against proteolytic degradation. It was postulated that RGTAs stimulate bone healing by interacting with HBGFs released in the wound site and, subsequently, by promoting the proliferation of cells implicated in this process. In a previous report, we examined how RGTA can modulate the proliferation of MC3T3-E1 osteoblastic cells. To further complete this study and to support this hypothesis, we developed an in vitro model of bone repair and examined the effects of RGTA alone or in association with FGF2, BMP-2, and TGF-beta1 which are representative of HBGFs known to stimulate bone repair. The model consisted of a 6-mm reproducible defect created on a MC3T3-E1 cell monolayer. In the presence of the different products added to the medium, the process of wound repair was measured through the filling of the acellular defect. We show that in 8 days, RGTA slightly inhibits repair alone compared to the control (2% FBS), that it inhibits the mitogenic effect of FGF2, and that it amplifies the inhibitory effect of BMP-2 and TGF-beta1. Repair was realized by an association of cell migration and cell proliferation mechanisms. To determine the part played by each process, DNA synthesis was evaluated for cell proliferation using an immunodetection technique [to measure incorporation of 5-bromo-2-deoxyuridine (BrdU)], coupled with a computer-assisted image analysis. The results show that the presence of RGTA (1) amplified the number of labeled nuclei compared to the control, (2) added to FGF2 or TGF-beta1, it reduced the number of labeled nuclei compared to FGF2 or TGF-beta1 alone, and (3) in the presence of BMP-2, it amplified the number of labeled nuclei compared to BMP-2 alone. Proper interpretation of these data requires a better understanding of the mechanism of action of RGTA on bone healing.
    Journal of Biomedical Materials Research Part A 04/2003; 64(3):525-32. · 2.83 Impact Factor
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    ABSTRACT: RGTA is a family of chemically modified polymers that have been engineered to mimic the properties of heparan sulfates towards heparin binding growth factors. In vivo, RGTA stimulated tissue repair and protection when injected at the site of an injury. These properties have been reported in various models, suggesting a potential interest for therapeutic uses as a general tissue repair agent. We have focused our interest on RGTA(11), a dextran derivative that was shown to enhance, after a unique and local administration, muscle regeneration after total crushing. We first show that a single RGTA(11) systemic administration can be as efficient as a local injection for stimulating muscle regeneration. Using an H(3)-labeled RGTA(11) we have measured some pharmacokinetic parameters. Distribution volume was 51.81 mL, clearance was about 2 mL/min, and half-life was 94 min, giving a total elimination time of 11 h. We also demonstrate that RGTA(11) remains detectable in the body only after tissue injury. It was detected by autoradiography in the crushed muscle just after injury and remained at least for a week. These results provide a rational explanation for the long lasting effect of a single local or systemic injection of RGTA.
    Journal of Biomedical Materials Research 01/2003; 62(4):525-31.
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    ABSTRACT: Muscle regeneration occurs through the activation of satellite cells, which are stimulated to proliferate and to fuse into myofibers that will reconstitute the damaged muscle. We have previously reported that a family of new compounds called "regenerating agents" (RGTAs), which are polymers engineered to mimic heparan sulfates, stimulate in vivo tissue repair. One of these agents, RG1192, a dextran derivative substituted by CarboxyMethyl, Benzylamide, and Sulfate (noted CMBS, RGTA type), was shown to improve greatly the regeneration of rat skeletal muscle after severe crushing, denervation, and acute ischemia. In vitro, these compounds mimic the protecting and stabilizing properties of heparin or heparan sulfates toward heparin-binding growth factors (HBGFs). We hypothesized that RGTA could act by increasing the bioavailability of some HBGF involved in myoblast growth and thus asked whether RGTA would alter the ability of satellite cells to proliferate. Its effect was tested on primary cultures of rat satellite cells. The RG1192 stimulated the proliferation of satellite cells in vitro in a dose-dependent manner. It appeared to be as efficient as natural glycosaminoglycans (GAGs; heparan sulfate, dermatan sulfate, or keratan sulfate) in stimulating satellite cell proliferation but was about 100 times more efficient than heparin. RG1192 stimulated satellite cell proliferation by increasing the potency of fibroblast growth factor 2 and scatter factor-hepatocyte growth factor. It also partially restored myoblast proliferation of satellite cells with chlorate-induced hyposulfation. Taken together, our results explain to some extent the improving effect of RGTA with a CMBS structure, such as the RG1192, on muscle regeneration in vivo by providing support for the hypothesis that RGTA may act by increasing the potency of some HBGFs during the proliferation phase of the regenerating muscle.
    Journal of Biomedical Materials Research 11/2002; 62(1):46-55.
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    ABSTRACT: A family of chemically substituted biopolymers has been developed to protect and stabilize heparin binding growth factors and was shown to enhance tissue repair in various in vivo models. One of these compounds, a dextran derivative named RGTA11, was tested for its ability to treat acute gastritis and colic ulceration models induced by ethanol and acid. RGTA was not efficient in reducing nor in protecting against gastric acidic secretion compared to EGF. Ethanol gastritis measured by the alteration score of the injured mucosa was reduced by 56% with the oral administration of RGTA at doses of 100 microg/kg (p < 0.01). A similar effect was obtained by PGE2 at a similar dose. Alterations of the colic mucosa were reduced after 72 h by 75% after oral administration of RGTA11. RGTA presents both anti-inflammatory and tissue repair activities mediated by growth factor protection. These two properties would be beneficial for digestive ulcer treatment. The results presented here provide evidence for these effects.
    Journal of Biomedical Materials Research 07/2002; 60(3):497-501.
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    ABSTRACT: A water soluble and hydrolysable polyester derived from malic acid has been synthesized by copolymerization of three different malolactonic acid esters. Functional pendant groups have been selected to interact with and protect heparin binding growth factors (HBGF). Three β-substituted β-lactones have been synthesized by using aspartic acid as a chiral precursor and benzyl, allyl and butyl alcohols in the formation of the ester pendant groups. The terpolymer has been subjected to three consecutive different chemical modifications. This modified terpolymer, able to induce new bone formation in an in vivo model, has the same property as carboxymethyl benzylamide sulfonate dextrans (CMDBS). Consequently, the distribution of the lateral functional groups is more essential than the glucidic nature of the backbone to acquire biological efficiency.
    Comptes Rendus de l Académie des Sciences - Series IIC - Chemistry 01/1999; 2(7):393-401.