scholarly journals Local Application of Mineral-Coated Microparticles Loaded With VEGF and BMP-2 Induces the Healing of Murine Atrophic Non-Unions

2022 ◽  
Vol 9 ◽  
Author(s):  
M. Orth ◽  
T. Fritz ◽  
J. Stutz ◽  
C. Scheuer ◽  
B. Ganse ◽  
...  
Keyword(s):  
Western Blot ◽  
Bone Healing ◽  
Bone Repair ◽  
Bone Defects ◽  
Vascular Endothelial ◽  
Key Factors ◽  
Non Union ◽  
Morphogenetic Protein ◽  
Union Model ◽  
Endothelial Growth Factor

Deficient angiogenesis and disturbed osteogenesis are key factors for the development of nonunions. Mineral-coated microparticles (MCM) represent a sophisticated carrier system for the delivery of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2. In this study, we investigated whether a combination of VEGF- and BMP-2-loaded MCM (MCM + VB) with a ratio of 1:2 improves bone repair in non-unions. For this purpose, we applied MCM + VB or unloaded MCM in a murine non-union model and studied the process of bone healing by means of radiological, biomechanical, histomorphometric, immunohistochemical and Western blot techniques after 14 and 70 days. MCM-free non-unions served as controls. Bone defects treated with MCM + VB exhibited osseous bridging, an improved biomechanical stiffness, an increased bone volume within the callus including ongoing mineralization, increased vascularization, and a histologically larger total periosteal callus area consisting predominantly of osseous tissue when compared to defects of the other groups. Western blot analyses on day 14 revealed a higher expression of osteoprotegerin (OPG) and vice versa reduced expression of receptor activator of NF-κB ligand (RANKL) in bone defects treated with MCM + VB. On day 70, these defects exhibited an increased expression of erythropoietin (EPO), EPO-receptor and BMP-4. These findings indicate that the use of MCM for spatiotemporal controlled delivery of VEGF and BMP-2 shows great potential to improve bone healing in atrophic non-unions by promoting angiogenesis and osteogenesis as well as reducing early osteoclast activity.

Enhancement of Bone Healing by Local Administration of Carbon Nanotubes Functionalized with Sodium Hyaluronate in Rat Tibiae

2017 ◽  
Vol 204 (3-4) ◽  
pp. 137-149 ◽  
Author(s):  
Vanessa B. Andrade ◽  
Marcos A. Sá ◽  
Renato M. Mendes ◽  
Paulo A. Martins-Júnior ◽  
Gerluza A.B. Silva ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Bone Repair ◽  
Bone Matrix ◽  
Sodium Hyaluronate ◽  
Repair Process ◽  
Bone Defects ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Bone Trabeculae ◽  
Endothelial Growth Factor

It has been reported that carbon nanotubes (CNTs) serve as nucleation sites for the deposition of bone matrix and cell proliferation. Here, we evaluated the effects of multi-walled CNTs (MWCNTs) on bone repair of rat tibiae. Furthermore, because sodium hyaluronate (HY) accelerates bone restoration, we associated CNTs with HY (HY-MWCNTs) in an attempt to boost bone repair. The bone defect was created by a 1.6-mm-diameter drill. After 7 and 14 days, tibiae were processed for histological and morphometric analyses. Immunohistochemistry was used to evaluate the expression of vascular endothelial growth factor (VEGF) in bone defects. Expression of osteocalcin (OCN), bone morphogenetic protein-2 (BMP-2), and collagen I (Col I) was assessed by real-time PCR. Histomorphometric analysis showed a similar increase in the percentage of bone trabeculae in tibia bone defects treated with HY and HY-MWCNTs, and both groups presented more organized and thicker bone trabeculae than nontreated defects. Tibiae treated with MWCNTs or HY- MWCNTs showed a higher expression of VEGF. Treatment with MWCNTs or HY-MWCNTs increased the expression of molecules involved in the bone repair process, such as OCN and BMP-2. Also, HY- and MWCNT-treated tibiae had an increased expression of Col I. Thus, it is tempting to conclude that CNTs associated or not with other materials such as HY emerged as a promising biomaterial for bone tissue engineering.

Vascular endothelial growth factor synergistically enhances bone morphogenetic protein-4-dependent lymphohematopoietic cell generation from embryonic stem cells in vitro

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2275-2283 ◽  
Author(s):  
Naoki Nakayama ◽  
Jae Lee ◽  
Laura Chiu
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Es Cells ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Morphogenetic Protein ◽  
Endothelial Growth Factor

Abstract The totipotent mouse embryonic stem (ES) cell is known to differentiate into cells expressing the β-globin gene when stimulated with bone morphogenetic protein (BMP)-4. Here, we demonstrate that BMP-4 is essential for generating both erythro-myeloid colony-forming cells (CFCs) and lymphoid (B and NK) progenitor cells from ES cells and that vascular endothelial growth factor (VEGF) synergizes with BMP-4. The CD45+ myelomonocytic progenitors and Ter119+ erythroid cells began to be detected with 0.5 ng/mL BMP-4, and their levels plateaued at approximately 2 ng/mL. VEGF alone weakly elevated the CD34+ cell population though no lymphohematopoietic progenitors were induced. However, when combined with BMP-4, 2 to 20 ng/mL VEGF synergistically augmented the BMP-4-dependent generation of erythro-myeloid CFCs and lymphoid progenitors from ES cells, which were enriched in CD34+ CD31lo and CD34+CD45− cell populations, respectively, in a dose-dependent manner. Furthermore, during the 7 days of in vitro differentiation, BMP-4 was required within the first 4 days, whereas VEGF was functional after the action of BMP-4 (in the last 3 days). Thus, VEGF is a synergistic enhancer for the BMP-4-dependent differentiation processes, and it seems to be achieved by the ordered action of the 2 factors.

scholarly journals Future treatments for hereditary hemorrhagic telangiectasia

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Florian Robert ◽  
Agnès Desroches-Castan ◽  
Sabine Bailly ◽  
Sophie Dupuis-Girod ◽  
Jean-Jacques Feige
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Vascular Endothelial ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Receptor Like Kinase ◽  
Recent Developments ◽  
Frequent Mutations ◽  
Transcriptional Complex ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor

AbstractHereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations of ACVRL1 or ENG genes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the gene SMAD4 which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, recent progress has been made using drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway with the use of bevacizumab (anti-VEGF antibody). Furthermore, several exciting high-throughput screenings and preclinical studies have identified new molecular targets directly related to the signaling pathways affected in the disease. These include FKBP12, PI3-kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients.

scholarly journals CCAAT/Enhancer-Binding Protein β Mediates Oxygen-Induced Retinal Neovascularization via Retinal Vascular Damage and Vascular Endothelial Growth Factor

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Tingting Li ◽  
Xuan Cai ◽  
Xiangning Wang ◽  
Xueyan Zhang ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Western Blot ◽  
Binding Protein ◽  
Retinal Function ◽  
Vascular Damage ◽  
Vascular Endothelial ◽  
Protein Levels ◽  
Enhancer Binding Protein ◽  
Endothelial Growth Factor

Objective. To evaluate the role of CCAAT/enhancer-binding protein β (C/EBP β) in retinal neovascularization (RNV) in an oxygen-induced retinopathy (OIR) model. Methods. Rats with OIR were exposed to alternating hypoxic and hyperopic conditions for 14 days. Then, the rats with OIR were assigned randomly to groups that received intravitreal injections of either shRNA lentiviral particles targeting C/EBP β (LV.shC/EBP β) or control particles (LV.shScrambled). The effectiveness of transduction using intravitreal injection of C/EBP β shRNA was examined in rats with OIR. The retinal vascular damage and accumulation of RNV were determined by retinal fluorescein-dextran perfusion, retinal ADPase staining, and periodic acid-Schiff (PAS) staining. Retinal function was recorded by electroretinogram responses to full-field light flashes. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analyses were used to measure mRNA and protein levels of C/EBP β and vascular endothelial growth factor (VEGF). The expression of p-C/EBP β was also examined by western blot analyses. The location of C/EBP β expression in the retina was determined by immunohistochemistry. Results. In OIR rats, the expression levels of C/EBP β and VEGF were significantly increased at both the mRNA and protein levels (P<0.01). The p-C/EBP β expression was consistent with the level of C/EBP β. C/EBP β was predominantly localized to the ganglion cell layer (GCL) and the inner nuclear layer (INL). The retinal C/EBP β level was significantly reduced in tissues from rats with OIR transduced with LV.shC/EBP β compared with tissues from those transduced with LV.shScrambled (P<0.01). Compared with those of the rats with OIR in the LV.shScrambled group, nonperfused retinal areas, neovascular tufts, pericyte death, and the ratio of endothelial cells to pericytes in the LV.shC/EBP β group were significantly reduced. In OIR rats, retinal function was impaired. There was no significant change in retinal dysfunction between the LV.shC/EBP β group and the LV.shScrambled group. The levels of VEGF mRNA and protein in the LV.shC/EBP β group were also decreased significantly compared with those of the rats with OIR in the LV.shScrambled group (P<0.01). Conclusions. C/EBP β shRNA inhibits RNV in OIR. A potential mechanism may be that the activity of C/EBP β increases with its overexpression, which in turn aggravates the amount of the retinal vascular damage and promotes transcription of VEGF. C/EBP β might be a new therapeutic target for preventing RNV.

scholarly journals Comparative Evaluation of Bone Repair with Four Different Bone Substitutes in Critical Size Defects

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Gustavo Grossi-Oliveira ◽  
Leonardo P. Faverani ◽  
Bruno Coelho Mendes ◽  
Tárik Ocon Braga Polo ◽  
Gabriel Cury Batista Mendes ◽  
...  
Keyword(s):  
Bone Repair ◽  
Immunohistochemical Analysis ◽  
Bone Substitutes ◽  
Vascular Endothelial ◽  
Calvarial Bone ◽  
Critical Size Defects ◽  
Related Transcription Factor ◽  
Osteoconductive Property ◽  
Bovine Hydroxyapatite ◽  
Endothelial Growth Factor

This study evaluated the osteoconductive potential of four biomaterials used to fill bone defects. For this, 24 male Albino rabbits were submitted to the creation of a bilateral 8 mm calvarial bone defect. The animals were divided into four groups—bovine hydroxyapatite, Bio-Oss® (BIO); Lumina-Bone Porous® (LBP); Bonefill® (BFL); and an alloplastic material, Clonos® (CLN)—and were euthanized at 14 and 40 days. The samples were subjected to histological and histometric analysis for newly formed bone area. Immunohistochemical analysis for Runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF), and osteocalcin (OC) was performed. After statistical analysis, the CLN group showed greater new bone formation (NB) in both periods analyzed (p<0.05). At 14 days, the NB showed greater values in BIO in relation to LBP and BFL groups; however, after 40 days, the LBP group surpassed the results of BIO (p<0.001). The immunostaining showed a decrease in Runx2 intensity in BIO after 40 days, while it increased for LBP (p<0.05). The CLN showed increased OC compared to the other groups in both periods analyzed (p<0.05). Therefore, CLN showed the best osteoconductive behavior in critical defects in rabbit calvaria, and BFL showed the lowest osteoconductive property.

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