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 (flt1TK−/−) and compared with age-matched wild-type (flt1TK+/+) 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 flt1TK−/− mice compared with those in flt1TK+/+ mice. The value of trabecular bone volume (BV/TV) was also significantly reduced in flt1TK−/− mice compared with that in flt1TK+/+ mice. The values of osteoclast surface (Oc.S/BS) and osteoclast number (Oc.N/BS) in flt1TK−/− mice were somewhat lower than those in flt1TK+/+ mice. The values of bending load of the femur significantly decreased in flt1TK−/− mice. In addition, serum osteocalcin significantly decreased in flt1TK−/− mice compared with those in flt1TK+/+ mice. Furthermore, there was a significant decreased mineralization of bone marrow stromal cultures from flt1TK−/− mice. These findings demonstrate that flt1TK−/− mice show lower trabecular bone volume than flt1TK+/+ mice, providing powerful evidence that vascular endothelial growth factor signal pathway through the Flt-1 tyrosine kinase domain could be implicated in osteoblast development.