VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice
VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice
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DOI：
10.1073/pnas.0503544102
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发表时间：
2005-09-27
影响因子：
11.1
通讯作者：
Shibuya, M
中科院分区：
文献类型：
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作者：
Niida, S;Kondo, T;Shibuya, M
VEGF受体1 （VEGFR-1/Flt-1）是VEGF的高亲和力酪氨酸激酶（TK）受体，调节血管生成以及单核细胞/巨噬细胞功能。我们之前的研究表明，成骨性Csf1(op)/Csf1(op) （op/op）小鼠的破骨细胞缺乏症以内源性vegf依赖的方式逐渐恢复。然而，恢复的分子基础仍然不清楚。为了研究哪个VEGFR是重要的，并阐明集落刺激因子1（CSF-1）和VEGF信号如何在破骨细胞形成中相互作用，我们在op/op小鼠中引入了VEGFR-1信号缺陷(F1t1（TK-)/(-)）。原始FlT1（TK-/-）小鼠表现出轻度破骨细胞减少，但没有骨髓抑制。然而，双突变(op/opFlt1（TK-)/(-)）小鼠表现出非常严重的破骨细胞缺乏，并且没有足够数量的破骨细胞形成骨髓腔。op/opFlt1(TK-)/(-)小鼠狭窄的骨髓腔逐渐被纤维组织取代，导致严重的骨髓发育不全和髓外造血。除破骨细胞外，op/opFlt1(TK-)/(-)小鼠的成骨细胞数量也减少。这些结果强烈提示，通过VEGFR-1和CSF-1受体的信号相互作用不仅在破骨细胞形成中起主导作用，而且在维持骨髓功能中也起主导作用。
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.