Molecular Mechanisms Of Growth, Osteogenesis And Osteolysis.
Coordinator : J.P. Salles
The team studies diseases in relation with growth, endocrine mechanisms and inflammatory status, as well as articular/bone diseases. We use cell (iPSC) and animal models and have access to biological resources issued from original cohorts of patients, specifically from rheumatoid arthritis and rare diseases, including patients with Noonan syndrome (NS), Prader Willi syndrome (PWS) and scoliosis. We are connected with reference centers for rare diseases and international networks. We develop original approaches of biotherapy, namely with phosphorus dendrimers.
Our first topic is to decipher the molecular mechanisms involved in growth and osteogenesis. We have developed models to study the molecular regulation of growth involving Ras/MAPK activation and IGF1 production in NS. We also study growth factors sensitivity and IGF1 production, oxytocin sensitivity in PWS. Lipid biochemistry is another topic, with study of the role of lysophosphatidic acid (LPA) in bone pathophysiology and in scoliosis. A new pathway involved synthesis of 2-arachidonoyl-glycerol involved in bone biology is also explored.
The second research aim is to investigate the mode of action of anti-TNF therapies in Chronic Arthritis (CA). We have developed strategies in order to decipher the pathophysiology of CA, and improve therapeutics approaches. Specific aims are understanding how monocytes and macrophages are polarized and differentiate into osteoclasts specialized in bone resorption and how anti-TNF and membrane induces reverse signaling and anti-inflammatory action in monocytes.
The third research aim is to decipher the pathophysiology of arthritis and develop new therapeutics based on dendrimers as anti-inflammatory agents. Anti-inflammatory properties of dendrimers in CA lead to striking effects in a mouse model of experimental arthritis and represent a promising therapeutical approach to target monocytes in inflammatory diseases.
The fourth research aim is to study the physiopathological mechanisms of neuroinflammation and bone inflammation in mucopolysaccharidoses (Sanfilippo Syndrome), as well as the development of several therapeutic approaches allowing on one hand to modulate the inflammation by trapping the extracellular vesicles and secondly by developing an intracranial and intravenous gene therapy program in order to sustainably provide the enzyme deficient in this pathology.
Axis 1: Pathophysiology and gene therapy for Sanfilippo syndrome, a paediatric neurodegenerative disease.
Workforce: S. Trudel-Ausseil, N. Ballout, C. Dias, M. Rouahi, C. Santiago, F. Briand-Mésange, H. Chap.
Sanfilippo syndrome (also referred as Mucopolysaccharidosis IIIB) is characterized by severe neuro-inflammation and neurodegeneration caused by the deficiency of a lysosomal exoglycanase leading to the interruption of heparan sulfate (HS) degradation. The progressive accumulation of HS Oligosaccharides (HSOs) induces oxidative stress development, cytokine and chemokine production via a TLR4-dependent activation in the central nervous system (CNS) (Trudel, J Neurosci Res 2015) and in the osteoarticular system. The activation of TLR-4 induces microglial STAT3 signalling pathway activation leading to increase expression of hepcidin and brain iron retention (Puy, Glia 2018). We are currently studying the functional and molecular status of microglia in this syndrome. We are also elucidating the role of microglia in the initiation and the propagation of inflammation leading to the neurodegenerative processes in our models (murine BV2 and primary adult microglia, human CHME-5 microglia and Sanfilippo B mouse models). Microglia-derived extracellular vesicle (EVs) are suggested to be involved in propagation of inflammatory signals in brain. However, little is known about the biogenesis and the regulation of EVs production. Using biochemical and proteomic approaches, we aim at studying the production, composition and role of EVs produced by microglia during neuro-inflammation.
The endocannabinoid system, which plays an important role in the regulation of numerous infectious and inflammatory pathologies, via the receptor CB2 (highly expressed in immune system) and CB1 (strongly expressed in the central nervous system) could have an important protective role in Sanfilippo syndrome . We recently discovered a new pathway for the synthesis of 2-arachidonoylglycerol (2-AG, mediated by a GDE3 enzyme, called AlterAG), the most potent agonist of both receptors. We are studying the implication of this new pathway in Sanfilippo syndrome and in other inflammatory and infectious pathologies, which could provide interesting new pharmacological targets to explore.
There is currently no therapy for these diseases. In collaboration with teams from the Institut Pasteur and the APHP, we participated in a first phase I / II clinical trial of intracerebral gene therapy on 4 Sanfilippo B children, the results of which are very encouraging. However, the neurocognitive benefit was only partial, probably because the enzyme is not delivered to the periphery of the brain. Our team is now launching a new preclinical study on animal models combining intracerebral and peripheral administration of a new vector crossing the blood brain barrier. If the results are convincing, a new clinical trial will be scheduled. This project is funded by the association Vaincre les Maladies Lysosomales.
AXIS 2: Regulation of monocytes / macrophages in inflammatory processes, bone remodeling, and therapeutics in arthritis
We have developed strategies in order to decipher the pathophysiology of chronic arthritis (CA), and improve therapeutics approaches. Our studies have focused on the need to circumvent adverse effects and the high cost of long-lasting treatments of CA such as anti-TNF biotherapies and on understanding their mode of action. Monocytes/macrophages, major components of inflammation and bone homeostasis, are targeted (Rev. Davignon et al., Rhumatol 2013).
Study of the anti-inflammatory impact of TNF-a reverse signaling in monocytes has shown that specific transcription factors are involved through the interaction of anti-TNF with transmembrane TNF (tmTNF) in monocytes in order to induce anti-inflammatory action through reverse signaling.
We are also is interested in monocytes differentiation into osteoclasts (OCs), multinucleated giant cells specialized in physiological and pathological bone resorption. The OCs activity is increased along rheumatoid arthritis (RA) leading to bone erosion and destruction.
We are studying the capacity of RA treatments (anti-TNF, JAK inhibitors) to modulate the polarization of macrophages in order to understand the mechanisms involved and improve RA treatment.
Coordinator: JL Davignon
Axis 3. Iron metabolism and hepcidin in chronic inflammatory diseases:
Iron that is present in all cells of the body, is necessary for life (oxygen transport, electron transfer reactions, or DNA synthesis). Physiological iron is used mainly to produce heme, the prosthetic group of hemoproteins such as hemoglobin, myoglobin and cytochrome P450. However, excess of iron represents a real threat for the cell since it is able to generate free radicals (ROS) during the Fenton reaction (chemical reaction using iron and oxygenated water to produce hydroxyl radical: H2O2 + Fe2+ “OH– + OH• + Fe3+). Iron is also incriminated to promote pathogen infection. In the body, iron balance is ensured by a strict equilibrium between its absorption from the diet and its storage by macrophages. Both intestinal absorption and macrophages release of iron are controlled by hepcidin, a small peptide synthesized and secreted by the liver. The expression of hepcidin is regulated by iron variations in the body (induced in iron overload and repressed by iron deficiency and stimulated erythropoiesis). In addition, being an acute phase protein, hepcidin in induced by inflammation, which in pathology contributes to functional iron deficiency and anemia of inflammation. Hepcidin is also expressed in many other organs, albeit at a much lower level (Kidney, brain, bone, monocytes/macrophages). The main goal of this axis is to develop research leading to elucidate the role of extrahepatic hepcidin in infection/inflammation process and in pathologies facing oxidative stress due to the uncontrolled inflammatory iron accumulation both in mouse models and in patients. Currently, our priorities is kidney diseases (anemia of inflammation, urinary tract infection), neuroinflammation (Sanfilippo syndrome) and bone/joint (Rheumatic disease).
Axis 4: Bone remodeling, arthritis and therapeutics:
Myeloid cells (monocytes, dendritic cells, macrophages and osteoclasts) play a central role in the pathogenesis of inflammatory osteo-articular diseases such as Rheumatoid Arthritis or Psoriatic Arthritis. They are notably involved in joint inflammation, structural damage, and inflammation-induced osteoporosis.
We aim at better characterizing the involvement of myeloid cells and at investigating the impact of disease-modifying anti-rheumatic drugs (DMARDs) on these cells in inflammatory rheumatic diseases. For this purpose, we are investigating:
– the mechanisms of TNF reverse signalling induced by anti-TNF agents and its implication in clinical response to anti-TNF agents;
– the role of hepcidin in joint inflammation and bone remodelling during arthritis;
– the impact of DMARDs on macrophage polarization and osteoclastogenesis in the context of inflammatory osteo-articular diseases.
Our strong connection to the Rheumatology department of Toulouse University Hospital and to the national Rheumatology network of University Hospitals allows an access to local (BIOTOUL) and national clinical databases and biobanks involving patients with Rheumatoid arthritis (ESPOIR cohort), Psoriatic Arthritis (APACHE cohort), Spondyloarthritis (DESIR cohort) and Systemic mastocytosis (CEREMAST).
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Possible Role of Adipose Tissue and the Endocannabinoid System in Coronavirus Disease 2019 Pathogenesis: Can Rimonabant Return? Journal Article
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The team is dedicated to the study of the mechanisms involved in the control of growth, bone formation and bone resorption, osteoporosis and the mechanisms of inflammation involved in chronic diseases including rheumatoid arthritis. An important component regards rare diseases in the field of pediatric endocrinology and mineral and bone metabolism, inserted into the French and European network for rare diseases, and rheumatology. The team is a referent for the Prader Willi syndrome and for diseases of the metabolism of calcium and phosphate.
Several protocols in progress are linked to clinical research trials. The response to hormones, growth hormone and IGF1 gives rise to ongoing trials, including the effect of statins in Noonan syndrome. With regard to Prader Willi syndrome (SPW), neuro-endocrine abnormalities have been linked to cellular mechanisms concerning the effect of growth hormone and IGF1 but also that of ghrelin and oxytocin. Original protocols for the use of oxytocin in SPW in young children are underway. We study also lysolipides, the role of lysophosphatidic acid involved in the development of adolescent scoliosis and a new pathway of production of endogenous cannabinoids related to the inflammatory response.
The study of original phosphorus dendrimers as immuno-modulators molecules targeting human monocytes by activating them towards an anti-inflammatory response, is another important theme of the team which has produced innovative medicines for the treatment of inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. One of these molecules is currently in preclinical development.
Finally, research on rheumatoid arthritis is oriented towards improving biotherapies involving anti-TNF drugs that are used in these patients. Part of the team is studying cell proteins that could be new potential drugs to limit bone erosion in these patients. Animal models of arthritic mice are used. This is linked to the National Association for the Protection of Rheumatoid Arthritis, who aim to identify new treatments and new research strategies.
In total, the team is extremely articulated with clinical research experiments in pediatrics, in Children’s University Hospital in Toulouse and in the network of Pediatric Research Centers (CIC Network) and clinical research for the management of rheumatoid arthritis and chronic inflammation. It is very much in line with rare diseases networks and patient associations.
- Dr. Muriel BLANZAT, Laboratoire des IMRCP, Toulouse.
- Dr. Anne-Marie CAMINADE et Dr. Cédric-Olivier TURRIN, Laboratoire de Chimie de Coordination, Toulouse
- Dr. Nicolas FAZILLEAU, équipe 4, CPTP, Toulouse
- Dr. Camille LAURENT, équipe 7 CRCT, Toulouse
- Pr. Bernard PAYRASTRE, équipe 11, I2MC, Toulouse
- Dr. Véronique PONS, équipe 8, l’I2MC, Toulouse
- Dr. Abdelhadi SAOUDI, équipe 5, CPTP, Toulouse
- Dr. Guillaume TABOURET, École Nationale Vétérinaire de Toulouse, INRA UMR1225, Toulouse
- Dr. Armelle YART, équipe 3, l’I2MC, Toulouse
- Dr. Daniel BOUVARD, Institut Albert Bonniot, Site Santé, GRENOBLE.
- Dr. Hélène CAVÉ, Département de Génétique, CHU Paris – Hôpital Robert Debré, PARIS.
- Fabienne COURY, Département de Rhumatologie, centre hospitalier Lyon Sud, 69495 Pierre-Bénite; Université Lyon 1, 69000
- Lyon, INSERM, UMR1033, SFR Santé Lyon-Est, LYON.
- Dr. Olivier PEYRUCHAUD, INSERM, UMR1033, SFR Santé Lyon-Est, LYON.
- Pr. Jerold CHUN, the Scripps Research institute, Department of Neuroscience, California Campus, La Jolla, USA.
- Pr. Eduardo FERNANDEZ-MEGIA, « Centro Singular de Investigación en Química iolóxica e Materiais Moleculares » (CIQUS), Universidade de Santiago de Compostela, SPAIN.
- Dr. Jane GROGAN, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
- Dr. Andrey KRUGLOV, Dr. Sergei NEDOSPASOV, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. Lomonosov Moscow State University, Moscow, RUSSIA. German Rheumatism Research Center (DRFZ), Berlin, GERMANY.
- Pr. Rudolph LEIBEL, Division of Molecular Genetics and the Naomi Berrie Diabetes Center, Columbia University, NYC, USA.
- Dr. Giulio G. MUCCIOLI, Université catholique de Louvain, Bruxelles, BELGIUM.
- Dr. Giovanni M. PAVAN, University for Applied Sciences and Arts of Southern Switzerland (SUPSI), Manno, SWITZERLAND.
- Dr. V. Gaëlle ROULLIN, School of Pharmacy, university of Montréal, Québec, CANADA.
- Dr. Timofey ROZHDESTVENSKY, Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, GERMANY.