title: VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice.
abstract: VEGF receptor 1 (VEGFR-1/Flt-1) is a high-affinity tyrosine kinase (TK) receptor for VEGF and regulates angiogenesis as well as monocyte/macrophage functions. We previously showed that the osteoclast deficiency in osteopetrotic Csf1op/Csf1op (op/op) mice is gradually restored in an endogenous, VEGF-dependent manner. However, the molecular basis of the recovery is still not clear. To examine which VEGFR is important and to clarify how colony-stimulating factor 1 (CSF-1) and VEGF signals interact in osteoclastogenesis, we introduced a VEGFR-1 signaling deficiency (Flt1(TK)-/-) into op/op mice. The original Flt1(TK)-/- mice showed mild osteoclast reduction without bone marrow suppression. The double mutant (op/opFlt1(TK)-/-) mice, however, exhibited very severe osteoclast deficiency and did not have numbers of osteoclasts sufficient to form the bone marrow cavity. The narrow bone marrow cavity in the op/opFlt1(TK)-/- mice was gradually replaced with fibrous tissue, resulting in severe marrow hypoplasia and extramedullary hematopoiesis. In addition to osteoclasts, osteoblasts also decreased in number in the op/opFlt1(TK)-/- mice. These results strongly suggest that the interaction of signals by means of VEGFR-1 and the CSF-1 receptor plays a predominant role not only in osteoclastogenesis but also in the maintenance of bone marrow functions.
authors.affiliation: Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology, Aichi 474-8522, Japan. niida@nils.go.jp
authors.forename: Shumpei
authors.initials: S
authors.lastname: Niida
authors.forename: Takako
authors.initials: T
authors.lastname: Kondo
authors.forename: Sachie
authors.initials: S
authors.lastname: Hiratsuka
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hayashi
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000254:growth & development* / Q000473:pathology; D002450:Cell Communication; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D005260:Female; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D040281:Vascular Endothelial Growth Factor Receptor-1