BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry

Abstract

Bone morphogenetic protein-2 (BMP-2) is a potent growth factor affecting bone formation. While recombinant human BMP-2 (rhBMP-2) has been commercially available in cases of non-union fracture and spinal fusion in orthopaedics, it has also been applied to improve bone regeneration in challenging cases requiring dental implant treatment. However, complications related to an initially high dosage for maintaining an effective physiological concentration at the defect site have been reported, although an effective and safe rhBMP-2 dosage for bone regeneration has not yet been determined. In contrast to protein delivery, BMP-2 gene transfer into the defect site induces BMP-2 synthesis in vivo and leads to secretion for weeks to months, depending on the vector, at a concentration of nanograms per milliliter. BMP-2 gene delivery is advantageous for bone wound healing process in terms of dosage and duration. However, safety concerns related to viral vectors are one of the hurdles that need to be overcome for gene delivery to be used in clinical practice. Recently, commercially available gene therapy has been introduced in orthopedics, and clinical trials in dentistry have been ongoing. This review examines the application of BMP-2 gene therapy for bone regeneration in the oral and maxillofacial regions and discusses future perspectives of BMP-2 gene therapy in dentistry.

Keywords: animal experimentation; bone morphogenetic protein 2; bone regeneration; gene transfer technique.

Figure 1

(a) Extraction socket-healing process. (BC, blood clot; B, buccal; L, lingual; PM, provisional matrix. WB, woven bone; BM, bone marrow; H&E staining; original magnification 16×). Reproduced with permission from Araujo et al. [4]. Copyright © 2005. John Wiley and Sons. (b) Growth factors related to bone wound healing. (PDGF, platelet-derived growth factor; VEGF, Vascular endothelial growth factor; BMPs, bone morphogenetic proteins; TGF-β, Transforming growth factor-beta) Reproduced with permission from Hollinger et al. [5]. Copyright © 2008. Wolters Kluwer Health, Inc.

Figure 1

(a) Extraction socket-healing process. (BC, blood clot; B, buccal; L, lingual; PM, provisional matrix. WB, woven bone; BM, bone marrow; H&E staining; original magnification 16×). Reproduced with permission from Araujo et al. [4]. Copyright © 2005. John Wiley and Sons. (b) Growth factors related to bone wound healing. (PDGF, platelet-derived growth factor; VEGF, Vascular endothelial growth factor; BMPs, bone morphogenetic proteins; TGF-β, Transforming growth factor-beta) Reproduced with permission from Hollinger et al. [5]. Copyright © 2008. Wolters Kluwer Health, Inc.

Figure 2

Regeneration strategy for the reconstruction of periodontal tissue through gene therapy.

Figure 3

Effect of diabetes on BMP-2 production and bone regeneration of BMSCs. (A) BMP-2 secretion of AdBMP-2-transfected nBMSCs vs that of AdBMP-2-transfected dBMSCs. (‘‘*’’indicates a significant difference, with * p < 0.05, ** p < 0.01, and *** p < 0.001 (paired t-test)) (B) BMP-2 signaling pathway analyzed by western blotting. (‘‘*’’indicates a significant difference, with * p < 0.05, ** p < 0.01, and *** p < 0.001 (paired t-test)) (C) Bone regeneration by AdBMP-2-transfected nBMSCs vs that by AdBMP-2-transfected dBMSCs. (‘‘*’’ indicates a significant difference from the other groups (ANOVA with Tukey’s post hoc test, p < 0.001) and ‘‘#’’ indicates a significant difference from the other groups), non-diabetic bone marrow stromal cells, nBMSC; AdBMP-2-transfected nBMSCs, B2/nBMSCs; diabetic BMSCs, dBMSCs; AdBMP-2-transfected dBMSCs; B2/dBMSCs. Reproduced from Park et al. [32]. Copyright © 2018. Mary Ann Liebert Inc.

Figure 4

Bone regeneration and re-osseointegration around peri-implantitis defects by AdBMP-2/PDLSCs. Upper pannel: light microscopic (A,C,E) and confocal laser scanning microscopic (B,D,F) photographs of histological sections of each experimental group at 12 weeks (original magnification × 1.5). Lower panel: magnification of newly formed bone and re-osseointegration within defects (G,H,I; original magnification × 4), NB, new bone; HAP, hydroxyapatite particles; OB, old bone; bone labeling: 4 weeks (green), 8 weeks (orange); multiple stains and undecalcified ground sections; bar indicates bottom of defect. Reproduced with permission from Park et al. [39]. Copyright © 2014 Wiley Periodicals, Inc.