Adenoviral Mediated Mono Delivery of BMP2 is Superior to the Combined Delivery of BMP2 and VEGFA in Bone Regeneration in a Critical-sized Rat Calvarial Bone Defect

Overview

Journal Bone Rep

Date 2019 Jun 14

PMID 31193299

Citations 3

Authors

Sunita Sharma

Ying Xue

Zhe Xing

Mohammed A Yassin

Yang Sun

James B Lorens

Anna Finne-Wistrand

Dipak Sapkota

Kamal Mustafa

Affiliations

Soon will be listed here.

Abstract

Apart from osteogenesis, neovascularization of the defect area is an important determinant for successful bone healing. Accordingly, several studies have employed the combined delivery of VEGFA and BMP2 for bone regeneration. Nevertheless, the outcomes of these studies are highly variable. The aim of our study was to compare the effectiveness of adenoviral mediated delivery of BMP2 alone and in combination with VEGFA in rat bone marrow stromal cells (rBMSC) seeded on a poly(LLA--CL) scaffold in angiogenesis and osteogenesis using a critical-sized rat calvarial defect model. Both mono delivery of BMP2 and the combined delivery of a lower ratio of VEGFA and BMP2 (1:4) led to up-regulation of osteogenic genes ( and ) and increased calcium deposition , compared with the GFP control. Micro computed tomography (microCT) analysis of the rat calvarial defect at 8 weeks showed that the mono delivery of BMP2 (43.37 ± 3.55% defect closure) was the most effective in healing the bone defect, followed by the combined delivery of BMP2 and VEGFA (27.86 ± 2.89%) and other controls. Histological and molecular analyses supported the microCT findings. Analysis of the angiogenesis, however, showed that both mono delivery of BMP2 and combined delivery of BMP2 and VEGFA had similar angiogenic effect in the calvarial defects. Examination of the key genes related to host response against the adenoviral vectors showed that the current model system was not associated with adverse immune response. Overall, the results show that the mono delivery of BMP2 was superior to the combined delivery of BMP2 and VEGFA in healing the critical-sized rat calvarial bone defect. These findings underscore the importance of appropriate growth factor combination for the successful outcome in bone regeneration.

Citing Articles

Hydrogel contained valproic acid accelerates bone-defect repair via activating Notch signaling pathway in ovariectomized rats.

Tao Z, Li T, Xu H, Yang M J Mater Sci Mater Med. 2021; 33(1):4.

PMID: 34940936 PMC: 8702411. DOI: 10.1007/s10856-021-06627-2.

Brd4 Inactivation Increases Adenoviral Delivery of BMP2 for Paracrine Stimulation of Osteogenic Differentiation as a Gene Therapeutic Concept to Enhance Bone Healing.

Paradise C, De La Vega R, Galvan M, Carrasco M, Thaler R, van Wijnen A JBMR Plus. 2021; 5(10):e10520.

PMID: 34693189 PMC: 8520065. DOI: 10.1002/jbm4.10520.

Challenges in Bone Tissue Regeneration: Stem Cell Therapy, Biofunctionality and Antimicrobial Properties of Novel Materials and Its Evolution.

Riester O, Borgolte M, Csuk R, Deigner H Int J Mol Sci. 2020; 22(1).

PMID: 33375478 PMC: 7794985. DOI: 10.3390/ijms22010192.

References

Avivi A, Resnick M, Nevo E, Joel A, Levy A . Adaptive hypoxic tolerance in the subterranean mole rat Spalax ehrenbergi: the role of vascular endothelial growth factor. FEBS Lett. 1999; 452(3):133-40. DOI: 10.1016/s0014-5793(99)00584-0. View

Street J, Bao M, deGuzman L, Bunting S, Peale Jr F, Ferrara N . Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002; 99(15):9656-61. PMC: 124965. DOI: 10.1073/pnas.152324099. View

Peng H, Wright V, Usas A, Gearhart B, Shen H, Cummins J . Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest. 2002; 110(6):751-9. PMC: 151123. DOI: 10.1172/JCI15153. View

Ferrara N . VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002; 2(10):795-803. DOI: 10.1038/nrc909. View

Park J, Ries J, Gelse K, Kloss F, von der Mark K, Wiltfang J . Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer: a comparison of adenoviral vectors and liposomes. Gene Ther. 2003; 10(13):1089-98. DOI: 10.1038/sj.gt.3301960. View

Odelius K, Plikk P, Albertsson A . Elastomeric hydrolyzable porous scaffolds: copolymers of aliphatic polyesters and a polyether-ester. Biomacromolecules. 2005; 6(5):2718-25. DOI: 10.1021/bm050190b. View

Peng H, Usas A, Olshanski A, Ho A, Gearhart B, Cooper G . VEGF improves, whereas sFlt1 inhibits, BMP2-induced bone formation and bone healing through modulation of angiogenesis. J Bone Miner Res. 2005; 20(11):2017-27. DOI: 10.1359/JBMR.050708. View

Li G, Corsi-Payne K, Zheng B, Usas A, Peng H, Huard J . The dose of growth factors influences the synergistic effect of vascular endothelial growth factor on bone morphogenetic protein 4-induced ectopic bone formation. Tissue Eng Part A. 2009; 15(8):2123-33. PMC: 2811054. DOI: 10.1089/ten.tea.2008.0214. View

Kempen D, Lu L, Heijink A, Hefferan T, Creemers L, Maran A . Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials. 2009; 30(14):2816-25. DOI: 10.1016/j.biomaterials.2009.01.031. View

10.

Young S, Patel Z, Kretlow J, Murphy M, Mountziaris P, Baggett L . Dose effect of dual delivery of vascular endothelial growth factor and bone morphogenetic protein-2 on bone regeneration in a rat critical-size defect model. Tissue Eng Part A. 2009; 15(9):2347-62. PMC: 2792218. DOI: 10.1089/ten.tea.2008.0510. View

11.

Schonmeyr B, Soares M, Avraham T, Clavin N, Gewalli F, Mehrara B . Vascular endothelial growth factor inhibits bone morphogenetic protein 2 expression in rat mesenchymal stem cells. Tissue Eng Part A. 2009; 16(2):653-62. PMC: 2947933. DOI: 10.1089/ten.TEA.2009.0426. View

12.

Xue Y, Danmark S, Xing Z, Arvidson K, Albertsson A, Hellem S . Growth and differentiation of bone marrow stromal cells on biodegradable polymer scaffolds: an in vitro study. J Biomed Mater Res A. 2010; 95(4):1244-51. DOI: 10.1002/jbm.a.32945. View

13.

Gomes P, Fernandes M . Rodent models in bone-related research: the relevance of calvarial defects in the assessment of bone regeneration strategies. Lab Anim. 2010; 45(1):14-24. DOI: 10.1258/la.2010.010085. View

14.

Xing Z, Xue Y, Danmark S, Schander K, Ostvold S, Arvidson K . Effect of endothelial cells on bone regeneration using poly(L-lactide-co-1,5-dioxepan-2-one) scaffolds. J Biomed Mater Res A. 2010; 96(2):349-57. DOI: 10.1002/jbm.a.32989. View

15.

Danmark S, Finne-Wistrand A, Schander K, Hakkarainen M, Arvidson K, Mustafa K . In vitro and in vivo degradation profile of aliphatic polyesters subjected to electron beam sterilization. Acta Biomater. 2011; 7(5):2035-46. DOI: 10.1016/j.actbio.2011.02.011. View

16.

Song X, Liu S, Qu X, Hu Y, Zhang X, Wang T . BMP2 and VEGF promote angiogenesis but retard terminal differentiation of osteoblasts in bone regeneration by up-regulating Id1. Acta Biochim Biophys Sin (Shanghai). 2011; 43(10):796-804. DOI: 10.1093/abbs/gmr074. View

17.

Zhang W, Wang X, Wang S, Zhao J, Xu L, Zhu C . The use of injectable sonication-induced silk hydrogel for VEGF(165) and BMP-2 delivery for elevation of the maxillary sinus floor. Biomaterials. 2011; 32(35):9415-24. PMC: 3384686. DOI: 10.1016/j.biomaterials.2011.08.047. View

18.

Evans C . Gene delivery to bone. Adv Drug Deliv Rev. 2012; 64(12):1331-40. PMC: 3392363. DOI: 10.1016/j.addr.2012.03.013. View

19.

Freire M, Kim H, Kook J, Nguyen A, Zadeh H . Antibody-mediated osseous regeneration: the early events in the healing response. Tissue Eng Part A. 2012; 19(9-10):1165-74. DOI: 10.1089/ten.TEA.2012.0282. View

20.

Helmrich U, Di Maggio N, Guven S, Groppa E, Melly L, Largo R . Osteogenic graft vascularization and bone resorption by VEGF-expressing human mesenchymal progenitors. Biomaterials. 2013; 34(21):5025-35. DOI: 10.1016/j.biomaterials.2013.03.040. View