Fms-like tyrosine kinase (Flt)-4 signaling participates in osteoclast differentiation in osteopetrotic (op/op) mice. 2009

Natsumi Tsuka, and Masahide Motokawa, and Masato Kaku, and Toshitsugu Kawata, and Tadashi Fujita, and Junji Ohtani, and Hiroyuki Koseki, and Hiroko Sunagawa, and Yayoi Matsuda, and Sara Abedini, and Hidetaka Hayashi, and Kazuo Tanne
Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan. natsumi-t@hiroshima-u.ac.jp

Vascular endothelial growth factor (VEGF) induces osteoclast differentiation as well as neovascularization by binding to the fms-like tyrosine kinase (Flt)-1 and fetal liver kinase (Flk)-1 receptors. The Flt-4 receptor also plays an important role in angiogenesis and lymphangiogenesis. The purpose of this study was to investigate the functions of Flt-4 in the signaling pathway of osteoclast differentiation. We examined the expression of Flt-4 on osteoclast precursor cells (OCPs), and the ability of recombinant human (rh) VEGF-D, one of the ligands of Flt-4, to stimulate the phosphorylation of extracellular-regulated kinase1/2 (ERK1/2) and to activate the nuclear factor-kappa B (NF-kappaB) pathway in OCPs. The number of osteoclasts induced by injection of rhVEGF-D in osteopetrotic (op/op) mice was also evaluated in the absence or presence of neutralizing antibodies to Flt-4. Flt-4 expression was detected on OCPs at both gene and protein levels and stimulation of Flt-4 by rhVEGF-D might induce activation of mitogen-activated protein kinase (MAPK) and NF-kappaB pathways for induction of osteoclast differentiation. Moreover, the number of osteoclasts in op/op mice increased after injection of rhVEGF-D, but was significantly reduced by the injection of Flt-4 neutralizing antibodies. We have therefore shown that Flt-4 expressed on OCPs, might activate MAPK and NF-kappaB pathways and played an important role in osteoclast differentiation.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D010010 Osteoclasts A large multinuclear cell associated with the BONE RESORPTION. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in CEMENTUM resorption. Odontoclasts,Cementoclast,Cementoclasts,Odontoclast,Osteoclast
D010022 Osteopetrosis Excessive formation of dense trabecular bone leading to pathological fractures; OSTEITIS; SPLENOMEGALY with infarct; ANEMIA; and extramedullary hemopoiesis (HEMATOPOIESIS, EXTRAMEDULLARY). Albers-Schoenberg Disease,Marble Bone Disease,Osteosclerosis Fragilis,Albers-Schonberg Disease,Albers-Schonberg Disease, Autosomal Dominant,Albers-Schönberg Disease,Autosomal Dominant Osteopetrosis Type 2,Congenital Osteopetrosis,Marble Bones, Autosomal Dominant,Osteopetrosis Autosomal Dominant Type 2,Osteopetrosis, Autosomal Dominant 2,Osteopetrosis, Autosomal Dominant, Type II,Osteosclerosis Fragilis Generalisata,Albers Schoenberg Disease,Albers Schonberg Disease,Albers Schonberg Disease, Autosomal Dominant,Albers Schönberg Disease,Disease, Albers-Schoenberg,Disease, Albers-Schonberg,Disease, Albers-Schönberg,Disease, Marble Bone,Osteopetroses,Osteosclerosis Fragilis Generalisatas
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D016328 NF-kappa B Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA. Immunoglobulin Enhancer-Binding Protein,NF-kappa B Complex,Nuclear Factor kappa B,Transcription Factor NF-kB,kappa B Enhancer Binding Protein,Ig-EBP-1,NF-kB,NF-kappaB,Nuclear Factor-Kappab,Complex, NF-kappa B,Enhancer-Binding Protein, Immunoglobulin,Factor NF-kB, Transcription,Factor-Kappab, Nuclear,Ig EBP 1,Immunoglobulin Enhancer Binding Protein,NF kB,NF kappa B Complex,NF kappaB,NF-kB, Transcription Factor,Nuclear Factor Kappab,Transcription Factor NF kB
D042461 Vascular Endothelial Growth Factor A The original member of the family of endothelial cell growth factors referred to as VASCULAR ENDOTHELIAL GROWTH FACTORS. Vascular endothelial growth factor-A was originally isolated from tumor cells and referred to as "tumor angiogenesis factor" and "vascular permeability factor". Although expressed at high levels in certain tumor-derived cells it is produced by a wide variety of cell types. In addition to stimulating vascular growth and vascular permeability it may play a role in stimulating VASODILATION via NITRIC OXIDE-dependent pathways. Alternative splicing of the mRNA for vascular endothelial growth factor A results in several isoforms of the protein being produced. Vascular Endothelial Growth Factor,Vascular Endothelial Growth Factor-A,GD-VEGF,Glioma-Derived Vascular Endothelial Cell Growth Factor,VEGF,VEGF-A,Vascular Permeability Factor,Vasculotropin,Glioma Derived Vascular Endothelial Cell Growth Factor,Permeability Factor, Vascular
D042643 Vascular Endothelial Growth Factor D A vascular endothelial growth factor that specifically binds to VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2 and VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-3. In addition to being an angiogenic factor it can act on LYMPHATIC VESSELS to stimulate LYMPHANGIOGENESIS. It is similar in structure to VASCULAR ENDOTHELIAL GROWTH FACTOR C in that they both contain N- and C-terminal extensions that were not found in other VEGF family members. FIGF Protein,VEGF-D,Vascular Endothelial Growth Factor-D,c-fos-Induced Growth Factor,c fos Induced Growth Factor

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