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: Growth factors: molecular mechanisms involved in growth and osteogenesis
Molecular dysregulation of growth involving MAPK activation is present in Noonan syndrome (NS). Activating SHP2/PTPN11 mutation constitutes a model of resistance to growth hormone (GH). NS is a developmental disorder with heart abnormalities and short stature. We have demonstrated in cells from patients and in a model of NS mice that growth retardation may be linked to impaired production of IGF-I and overactivity of the Ras/MAPK signaling pathway. Ras/MAPK hyperactivation is also present achondroplasia, which has been another topic of the team.
We presently are testing the molecular mechanisms involved in regulation of IGF1 production in the growth plate of NS mice. New therapeutic approaches are developed with statins in vivo (national clinical research program PHRC) and in vitro, in collaboration with A. Yart (Inserm UMR 1048, Toulouse).
We have demonstrated the role of lysophosphatidic acid (LPA), a small lipid growth factor, in regulation of bone development, with osteoporosis and altered growth plate activity in a mice model with invalidation of LPA1 receptor. (Coll. J. Chun, Scripps Instit. La Jolla). The present program is developed in the context of an ANR grant (LYSBONE, Coll. with O. Peyruchaud, Inserm UMR 1033, Lyon) and Occitanie Region grant. It aims to clarify the specific role of LPA1 by means of mice models invalidated osteoblasts (bone formation) or osteoclasts (bone resorption) and its relationships with the effect parathormone (PTH). Studies of pathophysiology of idiopathic scoliosis are connected, with original resources from patients.
PWS is a rare neuro-developmental disease with a severe eating disorder and behavioral disturbances. We study PWS pathophysiology with approaches in in vivo (on-going clinical research studies and cellular models with iPSC, cells from PWS patients. This is in the context of the national reference center for PWS coordinated in Toulouse (M. Tauber). Specifically the role of a small nucleolar RNA, SNORD116, is studied with respect to neuroendocrine and endocrine abnormalities in PWS. We have recently contributed to the demonstration of the role of SNORD116 in the processing of several prohormones (Coll. R. Liebel, Columbia Un.). We are presently testing the role of SNORD116 in other molecular patterns involved in the regulation of the response to growth factors, namely GH and IGF 1. Especially programs regarding the dysregulation of oxytocin are developed (clinical, national research program PHRC, and basic studies).
A totally new topic regards a new pathway of synthesis of 2- arachidonoyl-glycerol (2-AG), ligand of CB1 and CB2 cannabinoid receptors. From biochemistry studies, we found that a specific enzyme catalyzes the conversion of lysophosphatidylinositol (LPI) to 2-AG. Its role in inflammatory processes is presently evaluated.
Coordinator: JP Salles
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: Biotherapy of inflammation by the use of phosphorus dendrimers
Dendrimers are hyperbranched, multivalent, nano-sized “tree-like” molecules synthesized through an iterative step-by-step process. Due to their controlled size and structure, they are widely used for biomedical purposes (imaging, tissue engineering, drug delivery). We have discovered that original phosphorus-based dendrimers (from the Laboratoire de Chimie de Coordination, in Toulouse, A.M. Caminade, C.O. Turrin) have immuno-modulatory and anti-inflammatory properties on the human myeloid lineage (monocytes/macrophages, and derived cells) in vitro (S Fruchon et al., J Leukoc Biol 2009 ; Y Degboé et al., Arthritis Ther Res 2014).
We have proven the efficacy of a phosphorus-based dendrimer capped with twelve AzaBisPhosphonate groups (dendrimer ABP) in mouse models of experimental arthritis (relevant to Rheumatoid Arthritis; M Hayder et al., Sci Transl Med 2011), and of experimental auto-immune encephalomyelitis (relevant to Multiple Sclerosis; M Hayder et al., Biomacromolecules 2015). We have also shown that the same molecule is active against acute inflammation in a rat model of uveitis (S Fruchon et al., Molecules 2013).
As dendrimers are very innovative nano-sized molecules but far from the standards of the pharmaceutical industry, we have already gathered preliminary data regarding general toxicity, and immuno-safety in animals (S Fruchon et al., Nanotoxicology 2015). Whereas the cellular effects of phosphorus dendrimers are well documented, we have to unravel the molecular mechanisms underlying their biological effects on the myeloid lineage. Recently, we have shown that the dendrimer ABP is recognized by specific receptor(s) at the surface of human monocytes (J Ledall et al., Nanoscale 2015). We have also shown that the anti-inflammatory properties of the phosphorus dendrimers are related to both their surface functions and their three-dimensional shape (AM Caminade et al., Nat Commun 2015).
All together, these results provide preclinical Proofs of Concept of the therapeutic efficacy and the safety of the dendrimer ABP. It is a promising drug-candidate for the treatment of chronic inflammatory diseases, and is currently under regulatory preclinical development.
Coordinator: R Poupot
AXIS 4: Pathophysiological mechanisms of neuroinflammation and bone inflammation in mucopolysaccharidoses, pediatric neurodegenerative diseases. Development of therapeutic options.
Lysosomal storage disorders (MSL) are a heterogeneous group of over 50 hereditary inborn errors, mostly due to enzyme synthesis defects. This deficiency results in substrate accumulation in lysosome leading to a multitude of clinical symptoms, including neuropathology and osteoarticular defects.
Belongs to this group, mucopolysaccharidoses (MPS) are due to the accumulation of glycosaminoglycans (GAG) in all tissues. This progressive accumulation induces pathological consequences including neurodegeneration, neuroinflammation, osteoarticular inflammation and major oxidative stress. In Sanfilippo syndrome (MPS type III), we have shown that neuroinflammation was directly caused by TLR4 receptor activation by the presence of heparan sulfate oligosaccharides (HSO, glycosaminoglycan accumulated in this syndrome). Our studies are currently focused on the mechanisms of the spread of neuroinflammation and bone inflammation. In particular, we study the role of extracellular vesicles (EVs) produced by all cell types allowing cell communication. These EVs are normally produced under physiological conditions but their number and composition are considerably modified in case of pathological situations. Among these EVs, exosomes (sizes comprised between 30 and 150 nm) have been described as major players in the transmission of neuroinflammation associated with neurodegenerative diseases. Their role and their involvement in the pathophysiology of mucopolysaccharidoses have never been studied. We therefore study the production, composition and role of EVs produced by glial cells and osteoblastic cells in inflammatory contexts. Finally, we develop therapeutic approaches by modulating inflammation by trapping EVs. We are also currently involved in a clinical trial by gene therapy in the brain of 4 MPSIIIB children.
Coordinator: Prof. Jérôme AUSSEIL
Int J Mol Sci, 20 (2), 2019, ISSN: 1422-0067 (Electronic) 1422-0067 (Linking).
European Journal of Endocrinology, 179 (6), p. 409–418, 2018.
Multivalent nanosystems: targeting monocytes/macrophages. Article de journal
International journal of nanomedicine, 13 , p. 5511–5521, 2018, ISSN: 1178-2013.
Growth Hormone Treatment for Prader-Willi Syndrome. Article de journal
Pediatric endocrinology reviews : PER, 16 (Suppl 1), p. 91–99, 2018, ISSN: 1565-4753.
Human Molecular Genetics, 27 (13), p. 2276–2289, 2018.
Molecules (Basel, Switzerland), 23 (6), 2018.
Endocrine Connections, 7 (5), p. 663–672, 2018.
Biomacromolecules, 19 (3), p. 712–720, 2018, ISSN: 1526-4602.
Nanoparticle-Based Strategies to Treat Neuro-Inflammation. Article de journal
Materials (Basel, Switzerland), 11 (2), p. 270, 2018, ISSN: 1996-1944.
AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial Article de journal
PLoS ONE, 13 (1), p. 1–19, 2018, ISSN: 19326203.
A model to characterize psychopathological features in adults with Prader-Willi syndrome Article de journal
American Journal of Medical Genetics, Part A, 176 (1), p. 41–47, 2018, ISSN: 15524833.
Glia, 66 (8), p. 1709-1723, 2018, ISSN: 1098-1136 (Electronic) 0894-1491 (Linking).
High urinary ferritin reflects myoglobin iron evacuation in DMD patients Article de journal
Neuromuscul Disord, 28 (7), p. 564-571, 2018, ISSN: 1873-2364 (Electronic) 0960-8966 (Linking).
J Transl Med, 16 (1), p. 248, 2018, ISSN: 1479-5876 (Electronic) 1479-5876 (Linking).
Nanomaterials (Basel, Switzerland), 7 (9), p. 251, 2017, ISSN: 2079-4991.
J Clin Invest, 127 (1), p. 293-305, 2017, ISSN: 1558-8238 (Electronic) 0021-9738 (Linking).
The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader–Willi Syndrome Article de journal
PEDIATRICS, 139 (2), p. e2 0162976, 2017.
Anal Bioanal Chem, 409 (5), p. 1257-1269, 2017, ISSN: 1618-2650 (Electronic) 1618-2642 (Linking).
J Neuropathol Exp Neurol, 76 (10), p. 883-897, 2017, ISSN: 1554-6578 (Electronic) 0022-3069 (Linking).
Arterioscler Thromb Vasc Biol, 37 (7), p. 1391-1401, 2017, ISSN: 1524-4636 (Electronic) 1079-5642 (Linking).
Lancet Neurol, 16 (9), p. 712-720, 2017, ISSN: 1474-4465 (Electronic) 1474-4422 (Linking).
Clin Chim Acta, 475 , p. 7-14, 2017, ISSN: 1873-3492 (Electronic) 0009-8981 (Linking).
Stem Cell Res, 17 (3), p. 526-530, 2016, ISSN: 1876-7753 (Electronic) 1873-5061 (Linking).
Arthritis Res Ther, 18 , p. 56, 2016, ISSN: 1478-6362 (Electronic) 1478-6354 (Linking).
Phys Chem Chem Phys, 18 (31), p. 21871-80, 2016, ISSN: 1463-9084 (Electronic) 1463-9076 (Linking).
Nanomedicine, 12 (8), p. 2321-2330, 2016, ISSN: 1549-9642 (Electronic) 1549-9634 (Linking).
Front Aging Neurosci, 8 , p. 154, 2016, ISSN: 1663-4365 (Print) 1663-4365 (Linking).
Eur J Hum Genet, 23 (2), p. 252-5, 2015, ISSN: 1476-5438 (Electronic) 1018-4813 (Linking).
J Bone Miner Res, 30 (8), p. 1369-76, 2015, ISSN: 1523-4681 (Electronic) 0884-0431 (Linking).
Scoliosis, 10 , p. 33, 2015, ISSN: 1748-7161 (Print) 1748-7161 (Linking).
The key role of the scaffold on the efficiency of dendrimer nanodrugs Article de journal
Nat Commun, 6 , p. 7722, 2015, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).
Nanotoxicology, 9 (4), p. 433-41, 2015, ISSN: 1743-5404 (Electronic) 1743-5390 (Linking).
Theoretical and experimental characterization of amino-PEG-phosphonate-terminated Polyphosphorhydrazone dendrimers: Influence of size and PEG capping on cytotoxicity profiles Article de journal
Journal of Polymer Science Part A: Polymer Chemistry, 53 (6), p. 761-774, 2015, ISSN: 0887624X.
Nanoscale, 7 (42), p. 17672-84, 2015, ISSN: 2040-3372 (Electronic) 2040-3364 (Linking).
J Mol Biol, 427 (4), p. 775-791, 2015, ISSN: 1089-8638 (Electronic) 0022-2836 (Linking).
Brain, 138 (Pt 2), p. 336-55, 2015, ISSN: 1460-2156 (Electronic) 0006-8950 (Linking).
J Neurosci Res, 93 (3), p. 424-32, 2015, ISSN: 1097-4547 (Electronic) 0360-4012 (Linking).
Int J Obes (Lond), 38 (9), p. 1234-40, 2014, ISSN: 1476-5497 (Electronic) 0307-0565 (Linking).
Modulation of pro-inflammatory activation of monocytes and dendritic cells by aza-bis-phosphonate dendrimer as an experimental therapeutic agent Article de journal
Arthritis Research and Therapy, 16 (R98), 2014.
Bone defects in LPA receptor genetically modified mice Article de journal
Biochim Biophys Acta, 1831 (1), p. 93-8, 2013, ISSN: 0006-3002 (Print) 0006-3002 (Linking).
Targeting monocytes/macrophages in the treatment of rheumatoid arthritis Article de journal
Rheumatology (Oxford), 52 (4), p. 590-8, 2013, ISSN: 1462-0332 (Electronic) 1462-0324 (Linking).
Molecules, 18 (8), p. 9305-16, 2013, ISSN: 1420-3049 (Electronic) 1420-3049 (Linking).
Proc Natl Acad Sci U S A, 109 (11), p. 4257-62, 2012, ISSN: 1091-6490 (Electronic) 0027-8424 (Linking).
Arthritis Care Res (Hoboken), 64 (6), p. 872-80, 2012, ISSN: 2151-4658 (Electronic) 2151-464X (Linking).
Bone, 49 (3), p. 395-403, 2011, ISSN: 1873-2763 (Electronic) 1873-2763 (Linking).
Joint Bone Spine, 78 (2), p. 179-83, 2011, ISSN: 1778-7254 (Electronic) 1297-319X (Linking).
Arthritis Rheum, 63 (3), p. 681-90, 2011, ISSN: 1529-0131 (Electronic) 0004-3591 (Linking).
A Phosphorus-Based Dendrimer Targets Inflammation and Osteoclastogenesis in Experimental Arthritis Article de journal
Sci. Transl. Med, 3 (81 81ra35), 2011.
A Phosphorus-Based Dendrimer Targets Inflammation and Osteoclastogenesis in Experimental Arthritis Article de journal
Sci. Transl. Med, 3 (81 81ra35), 2011.
Arthritis Res Ther, 12 (4), p. R142, 2010, ISSN: 1478-6362 (Electronic) 1478-6354 (Linking).
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.