Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair
Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair
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DOI：
10.1172/jci82585
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发表时间：
2016-02-01
影响因子：
15.9
通讯作者：
Olsen, Bjorn R.
中科院分区：
文献类型：
--
作者：
Hu, Kai;Olsen, Bjorn R.
成骨细胞源性VEGF对骨发育和出生后骨稳态非常重要。以前的研究表明，VEGF影响骨修复和再生;然而，它的工作机制尚未完全了解。在这项研究中，我们研究了成骨细胞源性VEGF在骨缺损愈合中的作用。结果表明，成骨细胞来源的VEGF在修复过程中的几个阶段起着关键作用。使用成骨细胞特异性缺失Vegfa的转基因小鼠，我们证明了VEGF在炎症阶段促进巨噬细胞募集和血管生成反应，并且在膜内骨化修复发生的区域中，血管生成和骨生成需要最佳水平的VEGF。VEGF可能在此过程中作为旁分泌因子发挥作用，因为成骨细胞谱系细胞中Vegfr 2的缺失增强了成骨细胞的成熟和矿化。此外，成骨细胞和肥大软骨细胞来源的VEGF刺激招聘的血管和破骨细胞，并促进软骨再吸收在修复部位在骨膜endochondrialossification阶段。最后，成骨细胞衍生的VEGF刺激破骨细胞形成的最后重建阶段的修复过程。这些发现为改善骨再生和治疗骨愈合缺陷的临床策略提供了基础。
Osteoblast-derived VEGF is important for bone development and postnatal bone homeostasis. Previous studies have demonstrated that VEGF affects bone repair and regeneration; however, the cellular mechanisms by which it works are not fully understood. In this study, we investigated the functions of osteoblast-derived VEGF in healing of a bone defect. The results indicate that osteoblast-derived VEGF plays critical roles at several stages in the repair process. Using transgenic mice with osteoblast-specific deletion of Vegfa, we demonstrated that VEGF promoted macrophage recruitment and angiogenic responses in the inflammation phase, and optimal levels of VEGF were required for coupling of angiogenesis and osteogenesis in areas where repair occurs by intramembranous ossification. VEGF likely functions as a paracrine factor in this process because deletion of Vegfr2 in osteoblastic lineage cells enhanced osteoblastic maturation and mineralization. Furthermore, osteoblast- and hypertrophic chondrocyte-derived VEGF stimulated recruitment of blood vessels and osteoclasts and promoted cartilage resorption at the repair site during the periosteal endochondral ossification stage. Finally, osteoblast-derived VEGF stimulated osteoclast formation in the final remodeling phase of the repair process. These findings provide a basis for clinical strategies to improve bone regeneration and treat defects in bone healing.