• Journal of Yeungnam Medical Science
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• v.20 no.2
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• pp.142-151
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• 2003

To induce bone formation at ectopic site by tissue engineering and gene therapy, we transplanted collagen sponges containing rhBMP-7 transduced HEK 293 cells in the hypodermis of nude mice. Bone formation was investigated by histological and electron microscopic method at 3, 6, and 9 weeks after transplantation. At 9 weeks after transplantation, eosinophilic bony tissue was observed in the implanted collagen sponge and was confirmed as bone tissue by Von Kossa stain. In the transmission electron microscopic observation, the cells in newly formed bone tissue had eccentrically located nucleus and well developed rough endoplasmic reticulum (rER). Therefore, the cells were evaluated as osteoblasts. Those results suggest that it is possible to form a bone tissue in the ectopic site by transplantation of rhBMP-7 transduced HEK 293 cells. This will be contributed to push more advanced gene therapy for bone formation. However, the HEK 293 cell is unable to apply to the clinical gene therapy. Therefore it is worth to find more compatible cells for clinical application. In addition, collagen sponge is considered as an excellent scaffold and/or carrier for gene therapy and a good biomaterial for tissue engineering.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5293-5299
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• 2013

Purpose: High levels of bone morphogenetic protein (BMPs) have been reported in patients with lung cancer. This study was conducted to assess correlations between serum BMP-2 levels and prognostic outcome in patients with non-small-cell lung cancer (NSCLC). Methods: Blood samples from 84 patients with advanced NSCLC and 42 healthy controls were analyzed and quantitated for serum BMP-2 levels before and after two cycles of chemotherapy using a commercially available ELISA kit. Results: The median level of BMP-2 was 146.9 pg/ml in patients with NSCLC vs. 87.7 pg/ml in healthy controls (P<0.01). A significant correlation was observed between pretreatment serum BMP-2 level and ECOG PS, disease stage and number of organs with metastases (P<0.05). Serum BMP-2 level decreased significantly in patients who achieved objective response after two cycles of chemotherapy. Multivariate analysis showed that increased BMP-2 level and advanced clinical stage were significantly correlated with poor prognosis. Conclusion: Thes erum BMP-2 level is positively correlated with clinical stage, ECOG PS and metastatic burden and may serve as an independent negative predictor for prognosis. Decreased BMP-2 after chemotherapy could be a reliable marker for efficacy of treatment.

• The Journal of the Korean dental association
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• v.52 no.4
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• pp.218-233
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• 2014

Bispbosphonates are a class of pharmaceutic agents, which induce apoptosis of osteoclast as well as impair osteoclastic activity to suppress bone resorption. Thus, bisphophonates are effectively used to treat osteoporosis, multiple myeloma and to prevent bone metastases of malignant cancer. However, recently dental disease have been reported associated with Bisphosphonates. Thus, there are a number of discussions about proper prevention and treatment of bisphosphonate-related osteonecrosis of jaw(BRONJ). Marshall R. Urist in 1965 made the seminal discovery that a specific protein, BMP(bone morphogenetic protein), found in the extracellular matrix of demineralized bone could induce bone formation newly when implanted in extraosseous tissues in a host. BMPs are multi-functional growth factors which are members of the transforming growth factor-beta super family and their ability is that plays a pivotal roll in inducing bone. About 18 BMP family members have been identified and characterized. Among of them, BMP-2 and BMP-7 have significant importance in bone development. In this study, patients of BRONJ were recieved who visited Department of oral and maxillofacial surgery, school of dentistry, Wonkwang university for past 3 years from 2011 to 2013. We focused on the results of the surgical intervention. We suggest that new strategy of treatment used to rhBMP-2 and LFA(Lidocaine-Fibrinogen-Aprotinin)-collagen scaffold for patients of BRONJ. The purpose of this paper is to give a brief overview of BMPs and to critically review the clinical data currently available on rhBMP-2 and LFA collage scaffold.

• Journal of Periodontal and Implant Science
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• v.35 no.2
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• pp.511-524
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• 2005

The regeneration of lost periodontal tissue is a major goal of therapy. Periodontal ligament cell(PDL) is a specialized connective tissue that connects cementum and alveolar bone to maintain and support teeth in situ and preserve tissue homoeostasis. Bone morphogenetic proteins(BMPs) have shown much potential in the reconstruction of the periodontum by stimulate new bone and new cementum formation. Limitiations of BMP administration to periodontal lesions is high dose delivery, BMP transient biological activity, and low bioavailability of factors at the wound site. Gene delivery method can be alternative treatment strategy to deliver BMPs to periodontal tissue. The purpose of this study is to investigate efficiency of BMP-2 gene delivery with cell-based therapy using PDL cells. PDL cell were transduced with adenoviruses encoding either BMP-2 or Lac-Z gene. To evaluate osteogenic activity of expressed BMP-2 on PDL cells, we investigated secreted BMP-2, cellular activity, ALPase, produced mineralized nodules. To evaluate collagen scaffold as carrier for transduced cell delivery, we examined morphology and secreted BMP-2 of transducd PDL cells on it. BMP-2 transducd PDL cells produced higher levels of BMP-2, ALPase, mineralized nodules than non transduced cells. Cellular activity of transduced cells was showed similar activity to non transduced cells. Transduce cells attached on collagen scaffold secreted BMP-2 at 7day and was showed similar morphology to non transduced cells. These results demonstrated that transduced PDL cells produced biologically active BMP-2 and collagen scaffold could be carrier of transducd cells.

• Journal of Periodontal and Implant Science
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• v.29 no.4
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• pp.765-785
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• 1999

Bone morphogenetic protein-2/4 (BMP-2/4) are members of Transforming Growth $Factor-{\beta}\;(TGF-{\beta})$ superfamily and they may differentiate the osteoprogenitor cell and induce formation of cartilage and bone in vivo. This study was performed to investigate the effects of bone morphogenetic protein-2/4 on the characteristics of rat periodontal ligament cells(RPDL) and rat calvaria cells(RCV). In the control group, the cells were cultured alone with Dulbeco's Modified Eagle's Medium contained with 20% fetal bovine serum, $100{\mu}/ml$ penicillin, $100{\mu}/ml$ streptomycin. In the experimental groups, recombinant human bone morphogenetic protein-2/4 (25ng, 100ng, 250ng/ml) were added into the above culture condition. And then each group was characterized by examing the cell proliferation at 1, 2, 3, 5, 7th day, the amount of total protein synthesis and alkaline phosphatase activity at 2, 5, 7th day. And also, the calcified nodule was examed. The results were as follows ; 1 . Both RCV and RPDL cells in both control and experimental groups proliferated during the entire experimental period, but there is no stastically significant difference according to the BMP-2/4 concentration. 2 . Amount of total protein synthesis of both cells in both groups was steadily increased until 5th day, but all experimental groups were significantly different from the control group at 7th day. 3. Alkaline phosphatase activity of both cells in both groups was increased during the entire experiment period. In RCV cells, the experimental group treated with 100ng/ml and 250ng/ml BMP-2/4 were significantly different from the control group at 7th day. In RPDL cells, the experimental group treated with 100ng/ml and 250ng/ml BMP-2/4 were significantly different from the control group at 5th day, and all experimental groups were significantly different from the control group at 7th day. 4. In the both of the cultured Rat Periodontal ligament and calvaria cell treated with BMP-2/4 to compared with control group, it revealed more rapid cell polarization, cell aggregation and hyperchromatic stained on HE agent, and even though only 1 day treated with BMP-2/4 both RPDL and RCV showed more rapid cell reaction than control group. More sensivitve cell reaction of RCV were observed than RPDL in this experiment. From the above results, we could conclude that BMP-2/4 influenced the induction, proliferation and differentiation of bone forming cells

• Journal of Periodontal and Implant Science
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• v.38 no.sup2
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• pp.325-334
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• 2008

Purpose: The carrier used as delivery agent for bone morphogenetic proteins(BMPs) should also act as a scaffold for new bone formation. Moreover, bone formation should be predictable in terms of the volume and shape. This study examined the osteogenic effect of macroporous biphasic calcium phosphate (MBCP) block combined with ePTFE membrane as a carrier for recombinant human bone morphogenetic proteins (rhBMP-2). In addition, the additive effect of ePTFE membrane on bone formation was evaluated. Materials and Methods: Eight-millimeter critical sized calvarial defects were created surgically in 28 male Sprague-Dawley rats. The animals were divided into 2 groups containing 14 animals each. The defects were treated with either rhBMP-2/MBCP block (rhBMP-2/MBCP group) or rhBMP-2/MBCP block/ePTFE membrane (rhBMP-2/MBCP/ePTFE group). A disc-shaped MBCP block (3 mm height and 8 mm diameter) was used as the carrier for the rhBMP-2 and ePTFE membrane was used to cover the rhBMP-2/MBCP block. The histologic and histometric parameters were used to evaluate the defects after 2- or 8-week healing period (7 animals/group/healing interval). Results: The level of bone formation in the defects of both groups was significantly higher at 8 weeks than that at 2 weeks (P < 0.05). The ePTFE membrane has no additional effect compared with the rhBMP-2/MBCP block only. However, at 8 weeks, rhBMP-2/MBCP/ePTFE group showed more even bone formation on the top of the MBCP block than the rhBMP-2/MBCP group. Conclusion: These results suggest that the ePTFE membrane has no additive effect on bone formation when a MBCP block is used as a carrier for rhBMP-2.

• Restorative Dentistry and Endodontics
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• v.25 no.2
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• pp.170-179
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• 2000

The rh-BMP-4 is a subgroup of TGF-${\beta}$ superfamily. The application of rh-BMP in alveolar bony defect was reported to new alveolar bone and new cementum formation. For minimized complications following tooth replantation, a operator must replant a tooth fast at the pertinent position. This study was to evaluate the effect of rh-BMP-4 on periodontal regeneration and root resorption following tooth replantation in rats. The 50 Sprague-Dawley rats weighting about 130gm were used in this study. The animals were divided into three groups. Group 1 ; immediate replantation after extraction : Group 2 ; replantation stored teeth extraction of first molar, the removal of periodontal ligament with collagenase, and etching with citric acid : Group 3 ; replantation stored teeth with treated rh-BMP-4 in mesial root. Experimental animals were sacrificed 3, 7, 14 days after replantation by heart infusion. The maxillae were removed, fixed, demineralized, dehydrated, infiltrated and embedded with JB-4 mixture. For light microscopic observation, 5 micron sections were cut and stained with toluidine blue. The results of this study were as follows : 1. After experimental 3 days, all groups were observed dead space between periodontum and root. 2. After experimental 7 days, group 1 and group 3 were observed filling periodontal fibers between alveolar bone and root but group 2 were not. 3. After experimental 7 days, group 3 were observed appearance of attached cementoblast like cell on root surface. Group 1 were observed regular arrangement of fibroblasts and collagen fibers at ${\times}400$ observation. 4. After experimental 14 days, all group were observed filling periodontal fibers between alveolar bone and root. Group 1 were observed normal arrangement of periodontal fibers. Group 3 were observed less abnormal arrangement of periodontal fibers. Group 2 were not observed functional normal arrangement of periodontal fibers. 5. After experimental 14 days, group 2 and 3 were observed several root resorption and irregular root surface but group 1 were not. These results suggest that the rh-BMP-4 can stimulate cementogenesis and enhance to attach collagen fibers.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.3
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• pp.143-147
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• 2006

Carthamus tinctorius L.is known to improve fracture healing, and bone morphogenetic proteins (BMPs) are associated with the formation and healing process of bone. BMP-2 and BMP-7 are two of the most important BMPs during the bone healing process. Human osteosarcoma MG63 cells and rats were used to determine the effects of Carthamus tinctorius L. extract (CTE) on BMP-2 gene expression. BMP-2 gene expression by CTE treatment in human osteosarcoma MG63 cells was not different from the control group until 8 hours of incubation, but was significantly higher, by 31%, than that of the control group at 16 hr of incubation. Microscopic findings of the 9th rib 3 weeks after fracture showed typical rimming of the osteoblast and immature bone formation in control and CTE groups. BMP-2 gene expression by in situ hybridization was remarkably increased by a CTE-supplemented diet in the fracture group compared to the control group. In conclusion, Carthamus tinctorius L. increased BMP-2 gene expression in human osteosarcoma cells and fractured bone. But further studies would be needed to elucidate the effect of CTE on fracture healing in vivo because our results did not show any evidence of healing improvement histologically $3^{rd}$ week after fracture.

• Imaging Science in Dentistry
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• v.34 no.1
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• pp.35-48
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• 2004

Purpose: To investigate the effect of rhBMP-2 on the healing of bone defect in the low calcium diet rat. Materials and Methods: To prepare the experimental model, control group was fed a normal diet and experimental group was fed a low calcium diet for 3 weeks. And then, 4 mm bicortical perforated bone defect was made on mandibular body of each rats. Experimental group was subdivided into two groups; experimental group 1 (rats given a low calcium diet before and after bone defect) and experimental group 2 (rats given a low calcium diet before and after bone defect with rhBMP-2 application). At 1, 3, 5 and 7 weeks after bone defect formation, the rats were terminated. The healing of bone defect was assessed by three-dimensional computerized tomography, soft x-ray radiography, and histopathological examination. Results : The wound healing of the bone defect for control group, experimental group 1, and experimental group 2 showed a increase from 3 weeks after bone defect formation. The experimental group 2 showed a more increase in healing amount than control group and experimental group 1 from 5 weeks after bone defect formation and the experimental group 2 showed a complete recovery of bone defect at 7 weeks after bone defect formation. Conclusion: The healing process of bone defect is accelerated by rhBMP-2 application in the low calcium diet rats.

• Journal of Periodontal and Implant Science
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• v.46 no.4
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• pp.244-253
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• 2016

Purpose: The aim of this study was to characterize the healing in the grafted calvarial defects of rats after adjunctive hyperbaric oxygen therapy. Methods: Twenty-eight male Sprague-Dawley rats (body weight, 250-300 g) were randomly divided into two treatment groups: with hyperbaric oxygen therapy (HBO; n=14) and without HBO (NHBO; n=14). Each group was further subdivided according to the bone substitute applied: biphasic calcium phosphate (BCP; n=7) and surface-modified BCP (mBCP; n=7). The mBCP comprised BCP coated with Escherichia-coli-derived recombinant human bone morphogenetic protein-2 (ErhBMP-2) and epigallocatechin-3-gallate (EGCG). Two symmetrical circular defects (6-mm diameter) were created in the right and left parietal bones of each animal. One defect was assigned as a control defect and received no bone substitute, while the other defect was filled with either BCP or mBCP. The animals were allowed to heal for 4 weeks, during which those in the HBO group underwent 5 sessions of HBO. At 4 weeks, the animals were sacrificed, and the defects were harvested for histologic and histomorphometric analysis. Results: Well-maintained space was found in the grafted groups. Woven bone connected to and away from the defect margin was formed. More angiogenesis was found with HBO and EGCG/BMP-2 (P<0.05). None of the defects achieved complete defect closure. Increased new bone formation with HBO or EGCG/BMP-2 was evident in histologic evaluation, but it did not reach statistical significance in histometric analysis. A synergic effect between HBO and EGCG/BMP-2 was not found. Conclusions: Within the limitations of this study, the present findings indicate that adjunctive HBO and EGCG/BMP-2 could be beneficial for new bone formation in rat calvarial defects.