VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice

VEGF receptor 1 (VEGFR-1/Flt-1) is a high-affinity tyrosine kinase (TK) receptor for VEGF and regulates angiogenesis as well as monocyte/ macro phage functions. We previously showed that the osteoclast deficiency in osteopetrotic Csf1(op)/Csf1(op) (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 (F1t1(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.