Flt-1 tyrosine kinase-deficient homozygous mice result in decreased trabecular bone volume with reduced osteogenic potential.
To clarify the role of Fms-like tyrosine kinase-1 (Flt-1) signaling in bone dynamics, we examined C57BL/6J mice, aged 6, 9 and 16 weeks, with disruption of the flt1 tyrosine kinase domain gene (flt1(TK-/-)) and compared with age-matched wild-type (flt1(TK+/+)) mice. Dynamic histomorphometric analysis confirmed a significant decrease in the values of mineralizing surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR/BS) in the trabecular bone of the proximal tibiae of flt1(TK-/-) mice compared with those in flt1(TK+/+) mice. The value of trabecular bone volume (BV/TV) was also significantly reduced in flt1(TK-/-) mice compared with that in flt1(TK+/+) mice. The values of osteoclast surface (Oc.S/BS) and osteoclast number (Oc.N/BS) in flt1(TK-/-) mice were somewhat lower than those in flt1(TK+/+) mice. The values of bending load of the femur significantly decreased in flt1(TK-/-) mice. In addition, serum osteocalcin significantly decreased in flt1(TK-/-) mice compared with those in flt1(TK+/+) mice. Furthermore, there was a significant decreased mineralization of bone marrow stromal cultures from flt1(TK-/-) mice. These findings demonstrate that flt1(TK-/-) mice show lower trabecular bone volume than flt1(TK+/+) mice, providing powerful evidence that vascular endothelial growth factor signal pathway through the Flt-1 tyrosine kinase domain could be implicated in osteoblast development.
Otomo
Hajime
H
Department of Orthopaedic Surgery, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Sakai
Akinori
A
Uchida
Soshi
S
Tanaka
Shinya
S
Watanuki
Makoto
M
Moriwaki
Sawako
S
Niida
Shumpei
S
Nakamura
Toshitaka
T
D000818:Animals; D015519:Bone Density / Q000502:physiology; D001842:Bone and Bones / Q000502:physiology*; D002478:Cells, Cultured; D005269:Femur / Q000000981:diagnostic imaging / Q000502:physiology; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D011859:Radiography; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology; D013977:Tibia / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency* / Q000235:genetics; D016474:Weight-Bearing / Q000502:physiology
D042461:Vascular Endothelial Growth Factor A; D015675:Osteocalcin; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1