Agnès Vignery, PhD, DDS

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). 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.

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 differentiation of osteoblasts, which form new bone in response to 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.

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

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