• BMB Reports
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• v.50 no.6
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• pp.308-317
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• 2017

Bone morphogenetic protein type 2 receptor (BMPR2) is one of the transforming growth $factor-{\beta}$ ($TGF-{\beta}$) superfamily receptors, performing diverse roles during embryonic development, vasculogenesis, and osteogenesis. Human BMPR2 consists of 1,038 amino acids, and contains functionally conserved extracellular, transmembrane, kinase, and C-terminal cytoplasmic domains. Bone morphogenetic proteins (BMPs) engage the tetrameric complex, composed of BMPR2 and its corresponding type 1 receptors, which initiates SMAD proteins-mediated signal transduction leading to the expression of target genes implicated in the development or differentiation of the embryo, organs and bones. In particular, genetic alterations of BMPR2 gene are associated with several clinical disorders, including representative pulmonary arterial hypertension, cancers, and metabolic diseases, thus demonstrating the physiological importance of BMPR2. In this mini review, we summarize recent findings regarding the molecular basis of BMPR2 functions in BMP signaling, and the versatile roles of BMPR2. In addition, various aspects of experimentally validated pathogenic mutations of BMPR2 and the linked human diseases will also be discussed, which are important in clinical settings for diagnostics and treatment.

• Journal of Periodontal and Implant Science
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• v.32 no.3
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• pp.501-521
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• 2002

The purpose of this study is to evaluate the influences of the bone morphogenetic protein (BMP) on the healing of periodontal ligament and alveolar bone after replantation of tooth, and to examine the possibility of its clinical application. 45 Sprague Dawley rats weighted about 100 gram were divided into 3 experimental groups by different dose of BMP. All the upper right and left 1st molar were extracted after 5 days feeding of 0.4% ${\beta}$-aminopropionitrile, and right molar were used as experimental group and left molar were used as control group. The root surface of experimental molar were treated with 25,50 and l00ng/ml of human recombinant Bone morphogenetic protein-4 (rh-BMP-4) with micropipet, and 1M Sodium hypochloride were used on control root surface. All the experimental animals were sacrificed as 1, 2, 4, 7 and 14 days after autoreplantation of upper 1st molar into their own position. The maxilla were disected included both side of 1st molar. The collected tissue were processed from demineralization to paraffin embeding as usual procedure, and the specimens were prepared with Hematoxylin-Eosin stain for the light microscopic evaluation. The results of this study were as follows : 1. There was no significant differences between control and experimental site on 1 and 2 days after replantation of tooth. In the case of 4th days, the evidence of tissue regeneration were observed on experimental site to compare the controls. New osteoid were revealed on high concentration of BMP at 7 days after replantation, and it became more obvious at 14 days, 2. The effect of the rh-BMP-4 coated on root surface was revealed slight influences for the prolifertion of cells of periodontium and tissue regeneration as dose-dependent pattern. 3. Bony ankylosis was observed between alveolar bone and root surface due to the remarkable amount of osteoid formation on the 14 days after replantation of root. In the conclusion, it was suggested that topical application of the rhBMP-4 on the root surface has influence on the periodontal ligament and alveolar bone. The application method of BMP on the root should be designed with calculation of proper concentration.

• Journal of Periodontal and Implant Science
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• v.46 no.5
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• pp.350-359
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• 2016

Purpose: The purpose of the present study was to evaluate the effectiveness of a minimal concentration of bone morphogenetic protein-2 (BMP-2) in terms of quantitative and qualitative analyses of newly formed bone in a rabbit maxillary sinus model. Methods: In 7 rabbits, sinus windows were prepared bilaterally. Biphasic calcium phosphate (BCP) loaded with 0.05 mg/mL BMP-2 was grafted into one sinus (the BMP group) and saline-soaked BCP was placed into the other (the control group) in each animal. The animals were allowed an 8-week healing period before being sacrificed. Specimens including the augmented area and surrounding tissues were then removed and evaluated both radiographically and histologically. Results: There was a difference in the mineralization of new bone between the groups. In the BMP group, the greater part of the new bone consisted of mature lamellar bone with an evident trabecular pattern, whereas the control group showed mostly woven bone, consisting only partially of lamellar bone. Histometrically, the area of new bone was significantly greater ($4.55{\pm}1.35mm^2$ vs. $2.99{\pm}0.86mm^2$) in the BMP group than in the control group (P<0.05); however, the total augmentation volumes were not significantly different between the groups. Conclusions: Within the limitations of this study, it can be suggested that a minimal concentration of BMP-2 (0.05 mg/mL) had an osteoinductive effect with accelerated mineralization in a rabbit sinus model using a BCP carrier.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.43 no.6
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• pp.373-387
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• 2017

Objectives: The purpose of this study was to introduce our three experiments on bone morphogenetic protein (BMP) and its carriers performed using the critical sized segmental defect (CSD) model in rat fibula and to investigate development of animal models and carriers for more effective bone regeneration. Materials and Methods: For the experiments, 14, 16, and 24 rats with CSDs on both fibulae were used in Experiments 1, 2, and 3, respectively. BMP-2 with absorbable collagen sponge (ACS) (Experiments 1 and 2), autoclaved autogenous bone (AAB) and fibrin glue (FG) (Experiment 3), and xenogenic bone (Experiment 2) were used in the experimental groups. Radiographic and histomorphological evaluations were performed during the follow-up period of each experiment. Results: Significant new bone formation was commonly observed in all experimental groups using BMP-2 compared to control and xenograft (porcine bone) groups. Although there was some difference based on BMP carrier, regenerated bone volume was typically reduced by remodeling after initially forming excessive bone. Conclusion: BMP-2 demonstrates excellent ability for bone regeneration because of its osteoinductivity, but efficacy can be significantly different depending on its delivery system. ACS and FG showed relatively good bone regeneration capacity, satisfying the essential conditions of localization and release-control when used as BMP carriers. AAB could not provide release-control as a BMP carrier, but its space-maintenance role was remarkable. Carriers and scaffolds that can provide sufficient support to the BMP/carrier complex are necessary for large bone defects, and AAB is thought to be able to act as an effective scaffold. The CSD model of rat fibula is simple and useful for initial estimate of bone regeneration by agents including BMPs.

• The Journal of Korean Medicine
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• v.23 no.2
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• pp.190-197
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• 2002

Objectives : This study was performed to examine the effect of Yukmigiwhang-tang kamibang, a mixture of oriental herbal extracts, on the transcription of bone fonnation genes, BMP4 (bone morphogenetic protein 4) and TG2 (transglutaminase-2). Methods : Bone-related cells, MG-63 (human male osteosarcoma), HOS-TE85 (human female osteosarcoma), and KG-l (bone marrow) were cultured with portions of Yukmigiwhang-tang kamibang and the transcription activities of bone-related genes, BMP4 (bone morphogenetic protein 4) and TG2 (transglutaminase-2), were determined by Reverse-Transcription Polymerase Chain Reaction (RT-PCR). Results : Transcription of BMP4 gene in HOS-TE85 cell increased up to 40% at 0.3% (v/v) of Yukmigiwhang- tang kamibang extract and that of TG2 gene in MG-63 cells also increased up to 40% at 0.3-0.4% of the same extract. Although it was less significant when compared to those in other cells, the transcription of BMP4 gene in KG-l cells also increased up to 10 to 25%. Conclusions : These results clearly demonstrated that Yukmigiwhang-tang kamibang have an effect on transcription activity of bone-related genes, TG2 and BMP4, suggesting that it may play an important role in bone formation.

• Journal of Periodontal and Implant Science
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• v.49 no.2
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• pp.114-126
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• 2019

Purpose: The aim of this study was to evaluate the enhancement of osteogenic potential of biphasic calcium phosphate (BCP) bone substitute coated with Escherichia coli-derived recombinant human bone morphogenetic protein-2 (ErhBMP-2) and epigallocatechin-3-gallate (EGCG). Methods: The cell viability, differentiation, and mineralization of osteoblasts was tested with ErhBMP-2-/EGCG solution. Coated BCP surfaces were also investigated. Standardized, 6-mm diameter defects were created bilaterally on the maxillary sinus of 10 male New Zealand white rabbits. After removal of the bony windows and elevation of sinus membranes, ErhBMP-2-/EGCG-coated BCP was applied on one defect in the test group. BCP was applied on the other defect to form the control group. The animals were sacrificed at 4 or 8 weeks after surgery. Histologic and histometric analyses of the augmented graft and surrounding tissue were performed. Results: The 4-week and 8-week test groups showed more new bone (%) than the corresponding control groups (P<0.05). The 8-week test group showed more new bone (%) than the 4-week test group (P<0.05). Conclusions: ErhBMP-2-/EGCG-coated BCP was effective as a bone graft material, showing enhanced osteogenic potential and minimal side effects in a rabbit sinus augmentation model.

• Journal of Veterinary Clinics
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• v.39 no.2
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• pp.59-64
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• 2022

A dog aged two years and seven months and a cat aged seven years were referred owing to fractures of long bones. Preoperative radiographs revealed comminuted bone fractures close to joints. Conventionally, long-bone fractures are treated using intramedullary pins, plate and screw systems, or an external fixator system. In cases of non-reducible fractures, various graft materials have been used in fracture treatments to stimulate bone repair. Here, recombinant human bone morphogenetic protein-2 (rhBMP-2) and a collagen membrane were applied. Four weeks after surgery, fractured bone fragments began to unite and the bone union was observed using radiography four months after surgery. No complications occurred related to grafted materials. We successfully applied rhBMP-2 and collagen membranes in two different species to support the healing process of comminuted fractures, according to the concept of guided bone regeneration.

• Journal of Periodontal and Implant Science
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• v.35 no.2
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• pp.263-269
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• 2005

Bone morphogenetic protein(BMP) and platelet-derived growth factor(PDGF) have been demonstrated tostimulate bone formation when applied locally in vivo. To explore whether or not the combined use of BMP and PDGF could have promotive effect and synergic interaction on bone formation in vivo, bone marrow mesenchymal stem cells were treated with BMP-2, PDGF-BB, or BMP-2 plus PDGF-BB, and then these cells were injected into the subcutaneous space on the dorsum of nude mice. The bone formation was evaluated after 12 weeks. Histomorphometric analysis demonstrated that the subcutaneous nodules formed in nude mice contained 25.3% newly formed bone in the BMP-2 treated cells, 14.4% newly formed bone in the PDGF-BB treated cells, and 8.9% newly formed bone in the RMP-2 plus PDGF-BB treated cells. The results showed that the combination of BMP-2 and PDGF-BB had neither a promotive effect nor synergic interact on bone formation in vivo.

• Molecules and Cells
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• v.37 no.3
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• pp.270-274
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• 2014

Lymphatic vessels are essential to regulate interstitial fluid homeostasis and diverse immune responses. A number of crucial factors, such as VEGFC, SOX18, PROX1, FOX2C, and GJC2, have been implicated in differentiation and/or maintenance of lymphatic endothelial cells (LECs). In humans, dysregulation of these genes is known to cause lymphedema, a debilitating condition which adversely impacts the quality of life of affected individuals. However, there are no currently available pharmacological treatments for lymphedema, necessitating identification of additional factors modulating lymphatic development and function which can be targeted for therapy. In this report, we investigate the function of genes associated with Bone Morphogenetic Protein (BMP) signaling in lymphatic development using zebrafish embryos. The knock-down of BMP type II receptors, Bmpr2a and Bmpr2b, and type I receptors, Alk3 and Alk3b, as well as SMAD5, an essential cellular mediator of BMP signaling, led to distinct lymphatic defects in developing zebrafish. Therefore, it appears that each constituent of the BMP signaling pathway may have a unique function during lymphatic development. Taken together, our data demonstrate that BMP signaling is essential for normal lymphatic vessel development in zebrafish.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1183-1186
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• 2012

Objective: To observe the effect of insulin-like growth factor-1 (IGF-1) on bone morphogenetic protein (BMP)-2 expression in hepatocellular carcinoma SMMC7721 cells. Methods: Cells were divided into blank control, IGF-1, IGF-1 + SB203580, and SB203580 groups. SB203580 was used to block the p38 MAPK signaling pathway. Changes in the expression of BMP-2, p38 MAPK, and phosphorylated p38, MERK, ERK and JNK were determined using reverse transcription polymerase chain reactions (RT-PCR) and Western blot analysis. Results: Protein expression of phosphorylated BMP-2, MERK, ERK, and JNK was significantly up-regulated by IGF-1 compared with the control group ($1.138{\pm}0.065$ vs. $0.606{\pm}0.013$, $0.292{\pm}0.005$ vs. $0.150{\pm}0.081$, $0.378{\pm}0.006$ vs. $0.606{\pm}0.013$, and $0.299{\pm}0.015$ vs. $0.196{\pm}0.017$, respectively; P<0.05). Levels of BMP-2 and phosphorylated MERK and JNK were significantly reduced after blocking of the p38MAPK signaling pathway ($0.494{\pm}0.052$ vs. $0.165{\pm}0.017$, $0.073{\pm}0.07$ vs. $0.150{\pm}0.081$, and $0.018{\pm}0.008$ vs. $0.196{\pm}0.017$, respectively; P<0.05), but such a significant difference was not observed for phosphorylated ERK protein expression ($0.173{\pm}0.07$ vs. $0.150{\pm}0.081$, P>0.05). Conclusion: IGF-1 can up-regulate BMP-2 expression, and p38 MAPK signaling pathway blockage can noticeably reduce the up-regulated expression. We can conclude that the up-regulatory effect of IGF-1 on BMP-2 expression is realized through the p38 MAPK signaling pathway.