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Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair
Kai Hu, Bjorn R. Olsen
Kai Hu, Bjorn R. Olsen
Published January 5, 2016
Citation Information: J Clin Invest. 2016;126(2):509-526. https://doi.org/10.1172/JCI82585.
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Research Article Bone biology Article has an altmetric score of 1

Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair

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Abstract

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.

Authors

Kai Hu, Bjorn R. Olsen

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Figure 8

Deletion of Vegfa in osteoblastic cells reduces periosteal callus remodeling at PSD28.

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Deletion of Vegfa in osteoblastic cells reduces periosteal callus remode...
(A) H&E-stained sections from Vegfafl/fl, Vegfafl/+ Osx-Cre, and Vegfa CKO mice showing periosteal callus remodeling at PSD28. Representative images from 5–6 mice for each genotype. (B) Left panels: 2D images of sagittal sections of injured tibiae. Right panels: 3D reconstruction of periosteal callus. Representative images from 5–6 mice. (C) Decreased callus thickness, calculated as distance from edge of periosteal callus to injured cortical bone normalized to total volume of corresponding tibial segment, in Vegfa CKO compared with Vegfafl/fl mice; n = 5–6. (D) Decreased BV/TV, total callus BV normalized to total volume of the corresponding tibial segment, in Vegfa CKO compared with Vegfafl/fl mice; n= 5–6. (E) Low density of TRAP+ osteoclasts, normalized to total length of callus bone, in Vegfa CKO compared with Vegfafl/fl mice; n = 4. Scale bars: 500 μm (A and B), 200 μm (E). ANOVA with Tukey’s post-hoc test (C and D) and unpaired 2-tailed Student’s t test (E) were used. *P < 0.01; **P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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