Agnès Vignery |
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Yale University School of Medicine Orthopaedics and Cell Biology Associate Professor |  |
Mailing Address330 Cedar Street TMP535A,B Yale School of Medicine New Haven, Connecticut 06510United States | Contact Information |
Qualifications
Ph.D., University of Paris V, 1975.
D.D.S., University of Paris VII, 1972.
Expertise and Research Interests
Research in our laboratory focuses on bone biology with particular emphasis on the fusion mechanism of macrophages, hence the differentiation of osteoclasts and giant cells, and on the targeted formation of new bone. We have kept an interest in studying further the immunosuppressive role of calcitonin gene-related peptide (CGRP).
1. Research in our lab focuses on the differentiation of osteoclasts, which are multinucleated macrophages that resorb bone, with particular emphasis on the fusion mechanism of their precursors that belong to the mononuclear phagocyte lineage. We have generated in vivo and in vitro macrophage fusion assays to clone MFR/SIRPalpha, the expression of which is transiently but highly induced in macrophages at the onset of fusion in vitro and in vivo. We have also reported CD47 as the ligand for MFR, and CD44 as a molecule highly but transiently expressed at the onset of fusion. Most recently, we showed that CD200 is highly expressed in osteoclasts, but only at the onset of fusion of macrophages, which do not express CD200. Our goal is to define the role of these molecules in the fusion of macrophages. We have used genome-wide cDNA microarrays to identify the genes that belong to the fusion machinery. We are in the process of studying the function of several of these genes. The understanding we gained about macrophage-macrophage fusion is being applied to studies on macrophage fusion with tumor cells and with somatic cells, such as hepatocytes.
2. One of the most recent research focus in our lab has been the development of a novel approach to target the formation of new bone to specific skeletal sites. This new technology combines stem cells, nano-material and PTH. We are in the process of translating the data generated in rats into larger animals, such as rabbits, and eventually in humans. We are most interested in studying the molecular mechanisms that mediate the formation of the new bone, which forms in response to the mechanical ablation of marrow.
3. The immunosuppressive role of calcitonin gene related peptide (CGRP), which is a neuropeptide encoded by the same gene as the hormone calcitonin, is a line of research that we still pursue. CGRP shares structural and functional homology with calcitonin. While calcitonin is a calcium regulatory hormone produced by C cells in the thyroid, CGRP is concentrated in sensory nerve endings in all tissues and organs. We reported that CGRP has potent immuno-suppressive activity in vivo, and in vitro by virtue of inhibiting T helper 1 lymphocytes to produce cytokines such as Interleukin 2. By targeting the expression of the CGRP gene to beta cells of the endocrine pancreas of NOD mice, which develop spontaneous diabetes, we have shown that CGRP prevents type I diabetes. This indicates that CGRP acts as a local immunoregulatory peptide. Our goal is to investigate how CGRP controls immune cells function and whether CGRP can be targeted in vivo, using genetic engineering or local delivery, so as to allow for the survival of transplanted organs, and treat chronic inflammatory and autoimmune diseases.
1. Research in our lab focuses on the differentiation of osteoclasts, which are multinucleated macrophages that resorb bone, with particular emphasis on the fusion mechanism of their precursors that belong to the mononuclear phagocyte lineage. We have generated in vivo and in vitro macrophage fusion assays to clone MFR/SIRPalpha, the expression of which is transiently but highly induced in macrophages at the onset of fusion in vitro and in vivo. We have also reported CD47 as the ligand for MFR, and CD44 as a molecule highly but transiently expressed at the onset of fusion. Most recently, we showed that CD200 is highly expressed in osteoclasts, but only at the onset of fusion of macrophages, which do not express CD200. Our goal is to define the role of these molecules in the fusion of macrophages. We have used genome-wide cDNA microarrays to identify the genes that belong to the fusion machinery. We are in the process of studying the function of several of these genes. The understanding we gained about macrophage-macrophage fusion is being applied to studies on macrophage fusion with tumor cells and with somatic cells, such as hepatocytes.
2. One of the most recent research focus in our lab has been the development of a novel approach to target the formation of new bone to specific skeletal sites. This new technology combines stem cells, nano-material and PTH. We are in the process of translating the data generated in rats into larger animals, such as rabbits, and eventually in humans. We are most interested in studying the molecular mechanisms that mediate the formation of the new bone, which forms in response to the mechanical ablation of marrow.
3. The immunosuppressive role of calcitonin gene related peptide (CGRP), which is a neuropeptide encoded by the same gene as the hormone calcitonin, is a line of research that we still pursue. CGRP shares structural and functional homology with calcitonin. While calcitonin is a calcium regulatory hormone produced by C cells in the thyroid, CGRP is concentrated in sensory nerve endings in all tissues and organs. We reported that CGRP has potent immuno-suppressive activity in vivo, and in vitro by virtue of inhibiting T helper 1 lymphocytes to produce cytokines such as Interleukin 2. By targeting the expression of the CGRP gene to beta cells of the endocrine pancreas of NOD mice, which develop spontaneous diabetes, we have shown that CGRP prevents type I diabetes. This indicates that CGRP acts as a local immunoregulatory peptide. Our goal is to investigate how CGRP controls immune cells function and whether CGRP can be targeted in vivo, using genetic engineering or local delivery, so as to allow for the survival of transplanted organs, and treat chronic inflammatory and autoimmune diseases.
Other Expertise
I wish to be contacted by interested students (medical, graduate or undergraduates) as a potential research mentor/thesis adviser.
Future Research
1. Studying the interaction between MFR-CD47, CD44 and CD200 in the fusion of macrophages
2. Identifying the genes that regulate the fusion and/or the multinucleation of macrophages, hence the differentiation of osteoclasts and giant cells
3. Defining the signaling pathways that control the formation of osteoclasts
4. Translate our targeted formation of bone in rats into rabbits
5. Defining the molecular pathways that lead to the differentiation of osteoblasts in vivo
2. Identifying the genes that regulate the fusion and/or the multinucleation of macrophages, hence the differentiation of osteoclasts and giant cells
3. Defining the signaling pathways that control the formation of osteoclasts
4. Translate our targeted formation of bone in rats into rabbits
5. Defining the molecular pathways that lead to the differentiation of osteoblasts in vivo
Industrial Relevance
1. Screen for small molecules that block/stimulate osteoclast differentiation / pre-osteoclast fusion / osteoclastic bone resorption
2. Screen for small molecules that stimulate osteoclast apoptosis
3. Screen for small molecules that promote the differentiation of osteoblasts in vivo
2. Screen for small molecules that stimulate osteoclast apoptosis
3. Screen for small molecules that promote the differentiation of osteoblasts in vivo
Keywords
COS Keywords:
Bone, Bone Marrow, Cancer or Carcinogenesis, Cell Biology, Cell Differentiation, Cytokines, Dentistry, Diabetes, Gene Expression, Genetic Engineering, Immunosuppression, Macrophage, Monoclonal Antibodies, Organ Transplantation, Orthopedics, Osteoporosis, Peptides, Physical Medicine and Rehabilitation, Rehabilitation or Therapy, Signal Transduction, Stem Cells.Additional Terms:
Bone Formation, Bone Marrow, CGRP, Calcitonin, Cancer Cells, Cell-Cell Fusion, Giant Cell, Macrophage, Osteoblast, Osteoclast, Osteoporosis, PTH, PTHRP, Signaling, Stem Cell.Languages
(Reading, Writing, Speaking)
English: (Fluent, Fluent, Fluent)
French: (Fluent, Fluent, Fluent)
Memberships
American Society for Bone and Mineral Research
American Society for Cell Biology
International Chinese Hard Tissue Society
Honors and Awards
2007, Organizer and co-Chair,
First Gordon Research Conference on,
Cell-Cell Fusion
2005-2005,
Pfizer-Yale Fellowship,
Pfizer
1992-1994,
Shannon Award,
NIH-NIAMS,
Yale University,
Immunosuppression
1987-1992,
Research Career Development Award,
NIH-NIAMS,
Yale University,
Osteoporosis
Previous Positions
1976-1979, Assistant Professor,
Universite Paris V,
School of Dentistry
Patents
Use soluble recombinant extracellular domain of CD200R or antibodies that block CD200R to prevent and/or repair bone loss. Agnès Vignery, Jun Li and Juan Ke, Inventors,
Patent Number: ,
2008,
Industry,
United States of America.
Method for bone augmentation. Kieran Murphy, Agnès Vignery, Nozer Mehat and James Gilligan, inventors,
Patent Number: 60/621060 pending,
2007,
Industry,
United States of America.
Method for fostering bone formation and preservation,
Patent Number: 60/571200 pending,
2006,
Industry,
United States.
Devices that guide bone formation,
Patent Number: 60/682456 pending,
2006,
Industry,
United States of America.
Pharmaceutical compositions containing calcitonin gene-related peptide (CGRP) and use thereof to ameliorate hyperimmune-mediated diseases and abnormal conditions,
Patent Number: 5858978,
1999,
Institution-owned,
United States of America.
Use of calcitonin gene-related peptide to regulate immune response,
Patent Number: 5635478,
1997,
Institution-owned,
United States of America.
Publications
- Kang H (2010) Important Roles of PI3Kγ in Osteoclastogenesis and Bone Homeostasis, Proceedings of the National Academy of Sciences USA, In Press
- Zhang Q (2010) Dramatic increase in cortical thickness induced by femoral marrow ablation followed by a three-month treatment with PTH in rats, Journal of Bone and Mineral Research, 25, 1350-1359
- Carlson J (2009) Role of MKP-1 in osteoclasts and bone homeostasis, American Journal of Pathology, 175, 1564-1573
- Carlson J (2009) Deletion of mitogen activated protein kinase phosphatase-1 (MKP-1) modifies the response to mechanical bone marrow ablation in a mouse model, Comparative Medicine, 175, 1564-1573
- Zhang, Q, Cuartas, E, Mehta, N, Gilligan, J, Ke, H-Z, Saltzman, WM, Kotas, M, Ma, M, Rajan, S, Chalouni, C, Carlson, J, Vignery, A (2008) Replacement of bone marrow by bone in rat femurs: the bone bioreactor, Tissue Engineering, 14 (2), 237-246
- Vignery Agnès (2008) Methods to fuse macrophages in vitro, Methods in Molecular Biology: Cell Fusion, Totowa, NJ, Humana Press, 383-395 pages (bookchapter)
- Vignery Agnès (2008) Macrophage fusion Molecular mechanisms, Methods in Molecular Biology: Cell Fusion, Totowa, NJ, Humana Press, 149-161 pages (bookchapter)
- Cui W, Cuartas E, Ke J, Zhang Q, Einarsson H, Sedgwick JD, Li J, VigneryA (2007) CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts, Proceedings of the National Academy of Sciences, USA, 104, 14436-14441
- Chen E., Grote E., Mohler W, Vignery A. (2007) Cell-Cell fusion, Febs Letters, 581, 2181-2193
- Schipani E, Ferrari S, Datta NS, McCauley LK, Vignery A, Bellido T, Strewler JG, Turner CH, Jiang Y, Seeman E (2006) Meeting Report from the 28th Annual Meeting of the American Society for Bone and Mineral Research, http://www.bonekey-ibms.org/cgi/content/full/ibmske;3/11/14, ASBMR, http://www.bonekey-ibms.org, BoneKEy-Osteovision, 14-50 pages
- Cui W, Zhang Ke J, Zhang Q, Ke H-Z, Chalouni C, Vignery A (2006) The Intracellular Domain of CD44 Promotes the Fusion of Macrophages, Blood, 107, 796-805
- Vignery A, Macrophage Fusion: the Making of Osteoclasts and Giant Cells, J Exp Med, 202, 337-340, 2005
- Vignery A, Macrophage Fusion: Are Somatic and Cancer Cells Possible Partners?, Trends in Cell Biology, 15, 188-193, 2005
- Li H, Cuartas E, Cui W, Choi Y, Crawford DT, Ke HZ, Kobayashi KS, Flavell RA, Vignery A, IRAK-M Is a Central Regulator of Osteoclast Differentiation and Activation, J Exp Med, 201, 1169-1177, 2005
- Vignery, A, La fusion des macrophages:partenaires des cellules somatiques et cancereuses?, Medecine/Sciences, 21, 1070-1075, 2005
- van Beek EM, Bühring H-J, Colonna M, Hamaguchi M, Howard CJ, Kasuga M, Liu Y, Matozaki T, Neel B G, Parkos CA, Sano S-I, Vignery A, Vivier E, Wright M, Zawatzky R, and Barclay AN (2005) A nomenclature for Signal Regulatory Protein Family Member, Journal of Immunology, 175, 7788-7789
- Lesclous P, Guez D, Baroukh B, Vignery A, Saffar JL, Histamine participates in the early phase of trabecular bone loss in ovariectomized rats, Bone, 34, 91-99, 2004
- Buehler J, Chappuis P, Saffar JL, Tsouderos Y, Vignery A., Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (macaca fascicularis), Bone, 29(2), 176-179, 2001
- Han X, Sterling H, Chen Y, Saginario C, Brown EJ, Frazier WA, Lindberg FP, Vignery A, CD47, a ligand for MFR, participates in macrophage multinucleation, Journal of Biological Chemistry, 275(48), 37984-37992, 2000
- Millet I, Phillips R, Sherwin RS, Ghosh S, Voll RE, Flavell RA, Vignery A, Rincon M, Inhibition of NF-kappaB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide, Journal of Biological Chemistry, 275, 15114-15121, 2000
- Vignery A, Osteoclasts and giant cells:macrophage-macrophage fusion mechanism, International Journal of Experimental Pathology, 81, 291-304, 2000
- Ballica R, Valentijn K, Khachatryan A, Guerder S, Kapadia S, Gundberg C, Gilligan J, Flavell RA, Vignery A, Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice, Journal of Bone and Mineral Research, 14(7), 1067-74, July 1999
- Millet I, McCarthy TL, Vignery A, Regulation of IL-6 production by prostaglandin E2 in fetal rat osteoblasts: role of protein kinase A signaling pathway, Journal of Bone and Mineral Research, 13, 1092-1100, 1998
- Saginario C, Sterling H, Beckers C, Kobayashi R-J, Solimena M, Ullu E, Vignery A, MFR, a putative receptor mediating the fusion of macrophages, Molecular and Cellular Biology, 18, 6213-6223, 1998
- Sterling H, Saginario C, Vignery A, CD44 occupancy prevents the fusion of macrophages, Journal of Cell Biology, 143, 837-847, 1998
- Millet I, Vignery A, The neuropeptide calcitonin gene-related peptide inhibits TNF-alpha but poorly induces IL-6 production by fetal rat osteoblasts, Cytokine, 9(12), 999-1007, December 1997
- Valentijn K, Gutow A P, Troiano N, Gundberg C, Gilligan J P, Vignery A, Effects of calcitonin gene-related peptide on bone turnover in ovariectomized rats, Bone, 21(3), 269-74, September 1997
- Khachatryan A, Guerder S, Palluault F, Cote G, Solimena M, Valentijn K, Millet I, Flavell R A, Vignery A, Targeted expression of the neuropeptide calcitonin gene-related peptide to beta cells prevents diabetes in NOD mice, Journal of Immunology, 158(3), 1409-16, February 1997
- Karine Valentijn, Andrew Gutow, Nancy Troiano, Caren Gundberg, James Gilligan, Agnès Vignery, Effects of calcitonin gene related peptide on bone turnover in ovariectomized rats, Bone, 21, 209-214, 1997
- Vignery A, McCarthy T L, The neuropeptide calcitonin gene-related peptide stimulates insulin-like growth factor I production by primary fetal rat osteoblasts, Bone, 18(4), 331-5, April 1996
- Saginario C, Qian H Y, Vignery A, Identification of an inducible surface molecule specific to fusing macrophages, Proceedings of the National Academy of Sciences (USA), 92(26), 12210-4, 19 Dec 1995
- Vignery A, Bone cell defects in osteogenesis imperfecta, Connective Tissue research, 313, 275-278, 1995
- Wang F, Millet I, Bottomly K, Vignery A, Calcitonin gene-related peptide inhibits interleukin 2 production by murine T lymphocytes, Journal of Biological Chemistry, 267(29), 21052-7, 15 Oct 1992
- Vignery A, Raymond M J, Qian H Y, Wang F, Rosenzweig S A, Multinucleated rat alveolar macrophages express functional receptors for calcitonin, American Journal of Physiology, 261(6 Pt 2), F1026-32, December 1991
- Vignery A, Wang F, Ganz M B, Macrophages express functional receptors for calcitonin-gene-related peptide, Journal of Cellular Physiology, 149(2), 301-6, November 1991
- Vignery A, Wang F, Qian H Y, Benz E J Jr, Gilmore-Hebert M, Detection of the Na(+)-K(+)-ATPase alpha 3-isoform in multinucleated macrophages, American Journal of Physiology, 260(5 Pt 2), F704-9, May 1991
- Vignery A, Niven-Fairchild T, Shepard M H, Recombinant murine interferon-gamma inhibits the fusion of mouse alveolar macrophages in vitro but stimulates the formation of osteoclastlike cells on implanted syngeneic bone particles in mice in viv, Journal of Bone and Mineral Research, 5(6), 637-44, June 1990
- Vignery A, Niven-Fairchild T, Ingbar D H, Caplan M, Polarized distribution of Na+,K+-ATPase in giant cells elicited in vivo and in vitro, Journal of Histochemistry and Cytochemistry, 37(8), 1265-71, August 1989
- Vignery A, Macrophage multinucleation is accompanied by the expression of new soluble and membrane antigens in mice, American Journal of Pathology, 135, 565-570, 1989
- Lang R, Vignery A, Jensen PS, Fibrogenesis imperfecta ossium with early onset - observations after 20 years of illness, Bone, 7, 237-246, 1986
- Baron R, Neff L, Nefussi JR, Tran Van P, Vignery A, Kinetic and cytochemical identification of osteoclast precursors and their differentiation into multi-nucleated osteoclasts, American Journal of Pathology, 122, 363--378, 1986
- Horowitz M, Baron R, Mart J, Andreoli M, Vignery A., Osteoclast Activating Factor is Distinct from the Monokine IL-1. 24 (S1) :162-164, 1985, British Journal of Rheumatology, 24(S1), 162-164, 1985
- Stewart AF, Hoecker JL, Mallett LE, Segre GV, Amatruda TT, Vignery A, Hypercalcemia in Pheochromocytoma: Evidence for a novel mechanism, Annals of Internal Medicine, 102, 776-779, 1985
- Baron R, Tross R, Vignery A., Evidence of sequential remodeling histomorphometry during skeletal maturation, Anatomical Record, 208, 137-145, 1984
- Insogna KL, Stewart AS, Vignery AMC, Weir EC, Namnum PA, Baron RE, Kirkwood JM, Deftos LM, Broadus AE, Biochemical and histomorphometric characterization of a rat model for humoral hypercalcemia of malignancy, Endocrinology, 114, 888-896, 1984
- Horowitz M, Vignery A, Gershon R, Baron R, T-cells are responsible for osteoclast activating factor (OAF) production in murine spleen cells, Proceedings of the National Academy of Sciences (USA), 81, 2181-2185, 1984
- Gewirtz AM, Stewart AF, Vignery A, Hoffman R., Hypercalcemia complicating acute myelogenous leukemia: A syndrome of multiple etiologies, British Journal of Haematology, 54, 133-141, 1983
- Baron R, Gertner JM, Lang R, Vignery A., Increased bone turnover with decreased bone formation by osteoblasts in children with Osteogenesis Imperfecta Tarda, Pediatric Research, 17, 204-207, 1983
- Rodan S, Insogna KL, Vignery AMC, Stewart AF, Broadus AE, D'Souza SM, Bertolini DR, Mundy GR, Rodan GA, Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells, Journal of Clinical Investigation, 72, 1511-1515, 1983
- Tran Van P, Vignery A, Baron R., Cellular kinetics of the bone remodeling sequence in the rat, Anatomical Record, 202, 445-451, 1982
- Stewart A, Vignery A, Silvergate A, Ravin N, LiVolsi V, Broadus A, Baron R, Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: Uncoupling of bone cell activity, JCEM, 55(2), 219-227, 1982
- Tran Van P, Vignery A, Baron R., An electron microscopic study of the bone remodeling sequence in the rat, Cell Tissue Research, 225, 283-292, 1982
- Nefussi JR, Vignery A, Puzas JE, Baron R., Histomorphometry and autoradiography of cultured fetal rat long bones, Anatomical Record, 204, 105-112, 1982
- Baron R, Vignery A., Behavior of osteoclasts during a rapid change in their number induced by high doses of parathyroid hormone or calcitonin in intact rats, Metab Bone Dis Rel Res, 2, 339-346, 1981
- Lang R, Milkman M, Jensen PS, Vignery A., Chronic treatment of Paget's disease of bone with synthetic human calcitonin, Yale Journal of Biology and Medicine, 54, 355-365, 1981
- Vignery A, Baron R., Dynamic histomorphometry of alveolar bone remodeling in the adult rat, Anatomical Record, 196, 191-200, 1980
- Puzas E, Vignery A, Rasmussen H., Isolation of specific bone cell types by free-flow electrophoresis, Calcified Tissue International, 27(263-268), 1979
- Vignery A, Baron R., The effects of parathyroid hormone on the osteoclastic pool and bone resorption and formation in rat alveolar bone, Calcified Tissue Research, 26, 23-28, 1978
- Baron R, Saffar J-L, Vignery A., Alveolar bone remodeling: Normal status and effects of PTX and PTH on the remodeling sequence and the osteoclastic pool, Calcified Tissue Research, 22S, 502-504, 1977
- Duflot Vignery A, Etude quantitative des effets de la parathyroidectomie sur le remaniement osseux et la migration physiologique des dents chez le rat, Journal de Biologie Buccale, 3, 337-350, 1975
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