Fracture vascularity and bone healing: A systematic review of the role of VEGF

Keramaris, Nikolaos C.; Calori, G.M.; Nikolaou, V.S.; Schemitsch, Emil H.; Giannoudis, Peter V.

doi:10.1016/s0020-1383(08)70015-9

Cited by 277 publications

(182 citation statements)

References 62 publications

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“…The model of angiogenesis, for example, did not consider the impact that gradients in growth factors within the callus might have had on blood vessel growth. In reality, the release of the growth factor VEGF by hypertrophic chondrocytes may play a key role in regulating angiogenesis during endochondral ossification (Keramaris et al, 2008). VEGF is a regulator of angiogenesis and has been linked with, among other features, the upregulation of vessel invasion into hypertrophic cartilage (Keramaris et al, 2008;Zelzer et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…In reality, the release of the growth factor VEGF by hypertrophic chondrocytes may play a key role in regulating angiogenesis during endochondral ossification (Keramaris et al, 2008). VEGF is a regulator of angiogenesis and has been linked with, among other features, the upregulation of vessel invasion into hypertrophic cartilage (Keramaris et al, 2008;Zelzer et al, 2004). This may provide an explanation for the over prediction of hypertrophic cartilage at day 20 in the model incorporating mildly impaired angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

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A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

O'Reilly

Hankenson

Kelly

2016

Biomech Model Mechanobiol

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While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by the local oxygen tension and substrate stiffness. This was updated to include conditions for oxygen regu- lated cell death and endochondral ossification. The updated algorithm was validated by using it within a model of normal fracture healing where it predicted the experimentally observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post fracture (dpf). Furthermore, it also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment the model predicted the experimentally observed reduction in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe angiogenic impairment predicted the development of fibrous and necrotic tissue within the callus. These results provide insight into how environmental factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that endochondral ossification during fracture healing is governed by the local oxygen tension.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

O'Reilly

Hankenson

Kelly

2016

Biomech Model Mechanobiol

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“…[7][8][9] The involvement of angiogenesis in the outcome of bone repair is widely recognized but not entirely explored. 10 Increased understanding of the role of angiogenesis in bone repair is also crucial for designing new therapies, including the use of bone scaffold, for promoting bone fracture healing. [11][12][13] In this context, it is desirable to develop a quantitative imaging technique for structure analysis of neomicrovessels that proliferate through newly formed bone.…”

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confidence: 99%

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

Matsumoto

Goto

Sato

2013

Laboratory Investigation

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Quantitative three-dimensional (3D) imaging of angiogenesis during bone repair remains an experimental challenge. We developed a novel contrast agent containing 0.07-to 0.1-mm particles of zirconium dioxide (ZrCA) and established subtraction mCT using synchrotron radiation (sSRCT) for quantitative imaging of angiogenesis and bone repair. This method was applied to a rat model of tibial bone repair 3 days (DAY3; n ¼ 2), 5 days (DAY5; n ¼ 8), or 10 days (DAY10; n ¼ 8) after drill-hole injury. Using the same drill-hole defect model, its potential use was illustrated by comparison of bone repair between hindlimbs subjected to mechanical unloading (n ¼ 6) and normal weight bearing (n ¼ 6) for 10 days. Following vascular casting with ZrCA, the defect site was scanned with 17.9-and 18.1-keV X-rays. In the latter, image contrast between ZrCA-filled vasculature and bone was enhanced owing to the sharp absorption jump of zirconium dioxide at 18.0 keV (k-edge). The two scan data sets were reconstructed with 2.74-mm voxel resolution, registered by mutual information, and digitally subtracted to extract the contrast-enhanced vascular image. K 2 HPO 4 phantom solutions were scanned at 17.9 keV for quantitative evaluation of bone mineral. Angiogenesis had already started, but new bone formation was not found on DAY3. New bone emerged near the defect boundary on DAY5 and took the form of trabecular-like structure invaded by microvessels on DAY10. Vascular and bone volume fractions, blood vessel and bone thicknesses, and mineralization were higher on DAY10 than on DAY5. All these parameters were found to be decreased after 10 days of hindlimb unloading, indicating the possible involvement of angiogenesis in bone repair impairment caused by reduced mechanical stimuli. In conclusion, the combined technique of sSRCT and ZrCA vascular casting is suitable for quantitative 3D imaging of angiogenesis and its surrounding bone regeneration. This method will be useful for better understanding the linkage between angiogenesis and bone repair.

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“…Angiogenesis is achieved by two hormonal pathways: the angiopoietin-and VEGF-mediated pathways (2,14). Vegf was identified previously as a coordinator of chondrocyte growth and bone formation in growth plates of juvenile mice (15).…”

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confidence: 99%

Fgf-9 is required for angiogenesis and osteogenesis in long bone repair

Behr

Leucht

Longaker³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

128

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Bone healing requires a complex interaction of growth factors that establishes an environment for efficient bone regeneration. Among these, FGFs have been considered important for intrinsic bonehealing capacity. In this study, we analyzed the role of Fgf-9 in long bone repair. One-millimeter unicortical defects were created in tibias of Fgf-9 +/− and wild-type mice. Histomorphometry revealed that half-dose gene of Fgf-9 markedly reduced bone regeneration as compared with wild-type. Both immunohistochemistry and RT-PCR analysis revealed markedly decreased levels of proliferating cell nuclear antigen (PCNA), Runt-related transcription factor 2 (Runx2), osteocalcin, Vega-a, and platelet endothelial cell adhesion molecule 1 (PECAM-1) in Fgf-9 +/− defects. μCT angiography indicated dramatic impairment of neovascularization in Fgf-9 +/− mice as compared with controls. Treatment with FGF-9 protein promoted angiogenesis and successfully rescued the healing capacity of Fgf-9 +/− mice. Importantly, although other pro-osteogenic factors [Fgf-2, Fgf-18, and bone morphogenic protein 2 (Bmp-2)] still were present in Fgf-9 +/− mice, they could not compensate for the haploinsufficiency of the Fgf-9 gene. Therefore, endogenous Fgf-9 seems to play an important role in long bone repair. Taken together our data suggest a unique role for Fgf-9 in bone healing, presumably by initiating angiogenesis through Vegf-a. Moreover, this study further supports the embryonic phenotype previously observed in the developing limb, thus promoting the concept that healing processes in adult organisms may recapitulate embryonic skeletal development.tibia | regeneration | tissue B one healing is an efficient regenerative process resulting in newly formed bone equivalent to the original tissue. It involves the interplay of numerous factors over the well-characterized cascade of phases, including inflammation, callus formation, and remodeling (1), which recapitulate aspects of skeletal development (2, 3). Among these factors, several members of the FGF ligands, including FGF-2, -9, and -18, as well their corresponding receptors FGFR1-3, have been identified previously as having a major role during skeletal development (4-12). Although their contribution during skeletal development is well established, less is known about FGFs in fracture healing. The recent identification of different expression patterns of FGF ligands and receptors during fracture repair (13) indicates potential functions in bone regeneration. Within the group of pro-osteogenic FGF ligands, Fgf-9 has been reported to play a role during the development of skeletal vascularization (11).Skeletal vascularization of the injury site is a key step in facilitating successful bone regeneration. Angiogenesis is achieved by two hormonal pathways: the angiopoietin-and VEGF-mediated pathways (2, 14). Vegf was identified previously as a coordinator of chondrocyte growth and bone formation in growth plates of juvenile mice (15). Moreover, Vegf is released physiologically in fracture hematoma (16). C...

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Fracture vascularity and bone healing: A systematic review of the role of VEGF

Cited by 277 publications

References 62 publications

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

Fgf-9 is required for angiogenesis and osteogenesis in long bone repair

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