• 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.49 no.4
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• pp.228-236
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• 2019

Purpose: The purpose of this study was to evaluate the synergistic effect of adjunctive hyperbaric oxygen (HBO) therapy on new bone formation and angiogenesis after 8 weeks of healing. Methods: Sprague-Dawley rats (n=28) were split into 2 groups according to the application of adjunctive HBO therapy: a group that received HBO therapy (HBO group [n=14]) and another group that did not receive HBO therapy (NHBO group [n=14]). Each group was divided into 2 subgroups according to the type of bone graft material: a biphasic calcium phosphate (BCP) subgroup and an Escherichia coli-derived recombinant human bone morphogenetic protein-2-/epigallocatechin-3-gallate-coated BCP (mBCP) subgroup. Two identical circular defects with a 6-mm diameter were made in the right and left parietal bones of each rat. One defect was grafted with bone graft material (BCP or mBCP). The other defect was not grafted. The HBO group received 2 weeks of adjunctive HBO therapy (1 hour, 5 times a week). The rats were euthanized 8 weeks after surgery. The specimens were prepared for histologic analysis. Results: New bone (%) was higher in the NHBO-mBCP group than in the NHBO-BCP and control groups (P<0.05). Blood vessel count (%) and vascular endothelial growth factor staining (%) were higher in the HBO-mBCP group than in the NHBO-mBCP group (P<0.05). Conclusions: HBO therapy did not have a positive influence on bone formation irrespective of the type of bone graft material applied after 8 weeks of healing. HBO therapy had a positive effect on angiogenic activity.

• 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 Veterinary Clinics
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• v.33 no.5
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• pp.300-303
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• 2016

An age-unknown, 4.8 kg, male, wild, domestic short-hair cat was presented for left hindlimb lameness. A physical examination revealed a draining tract which was suspected of bite on left calcaneal bone. The left tarsal joint was markedly swollen and exudates were observed around the draining tract. Sequestrum at left calcaneus bone, and osteolysis were identified by radiography. The sequestrum and its surrounding exudative tissue were debrided during surgery and the tissue was submitted for bacterial culture and sensitivity test. The debridement caused a bone defect ($1.5cm{\times}0.5cm{\times}0.5cm$) on the medial left calcaneal bone. Plate and screw fixation was performed to the calcaneus bone as buttress plate. Recombinant human bone morphogenetic protein-2 (rhBMP-2) loaded hydroxyapatite was implanted in the bone defect. Furthermore, Amikacin-impregnated collagen sponges were also placed around bone plate to deliver local antibiotics. A systemic antibiotic treatment regimen based on bacterial culture and sensitivity test results was administered for 4 weeks. The wound properly healed without any signs of infection, and the bone healing was confirmed by radiography. The patient showed normal weight bearing ambulation at 18 weeks after surgery. The use of rhBMP-2 and local antibiotic delivery system is a good surgical option for the one-stage treatment of chronic osteomyelitis.

• IMMUNE NETWORK
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• v.23 no.6
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• pp.48.1-48.21
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• 2023

Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSC^BMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSC^BMP2 were associated with migration and growth. MSC^BMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSC^BMP2. MSC^BMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3⁺CD25⁺ Treg of CD4⁺ cells were further increased in ALI mice treated with MSC^BMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSC^BMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSC^BMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.36 no.6
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• pp.466-472
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• 2010

Introduction: This study examined the effect of recombinant human bone morphogenetic protein (rhBMP)-2 and $\beta$-tricalcium phosphate ($\beta$-TCP) on new bone formation in a rabbit calvarium using a rapid prototype titanium cap (RP Ti cap). Materials and Methods: Eight New Zealand white rabbits were used in this study. Hemispherical RP Ti caps (10 mm in diameter) were implanted subperiosteally on the rabbit calvaria. $\beta$-TCP was filled in the RP Ti cap in the control group, and rhBMP-2 soaked $\beta$-TCP was used in experimental group. The rabbits were sacrificed 2 and 4 weeks after the operation. The volume and pattern of newly formed bone was analyzed by micro computed tomography (CT). Results: Macroscopically, there were no abnormal findings in any of the animals. The micro CT images revealed new bone from the calvaria that expanded gradually toward the top of the titanium cap, particularly along the inner surface of the titanium cap in the experimental group at 4 weeks after grafting. There was no significant difference in new bone volume ratio between the control and experimental groups at 2 weeks after grafting. There was a statistically significant difference in the new bone volume ratio between the experimental ($14.1{\pm}1.8\;%$) and control ($7.2{\pm}1.5\;%$) groups at 4 weeks after grafting (P<0.01). Conclusion: The RP Ti cap can effectively guide new bone formation and rhBMP-2 can induce the new bone formation.

• Asian Spine Journal
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• v.12 no.6
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• pp.1010-1016
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• 2018

Study Design: Retrospective cohort study. Purpose: To report on spinal fusion assessment using computed tomography (CT) after adult spinal deformity (ASD) surgery using ultra-low dose recombinant human bone morphogenetic protein 2 (RhBMP-2). Overview of Literature: The reported dose of RhBMP-2 needed for successful spinal posterolateral fusion in ASD ranges from 10 to 20 mg per spinal level. This study reports the use of ultra-low dose of RhBMP-2 (0.07 mg per facet) to achieve spinal fusion in multilevel ASD surgery. Methods: Consecutive patients who underwent ASD surgery using ultra-low dose RhBMP-2 were recruited. Routine postoperative CT analysis for spinal fusion was performed by two spine surgeons. Inter-observer agreement was calculated for facet fusion (FF) and interbody fusion (IBF) at 6 and 12 months after the procedure. Results: Six consecutive ASD patients with a mean age of 62 years (28-72 years) were examined. Each patient received a total dose of 12 mg with an average dose of $0.69{\pm}0.2mg$ (0.42-1 mg) per single FF and $1.38{\pm}0.44mg$ (0.85-2 mg) for IBF. Total 131 FF and 15 IBF were examined in the study, with 88 FFs and nine IBFs being analyzed specifically at 6 months after the surgery. FF and IBF reported by surgeons A and B at 6 months were 97.7% vs. 91.9% FF, respectively (${\kappa}=0.95$) and 100% vs. 100% IBF, respectively (${\kappa}=1$). Two patients underwent longitudinal follow-up CT at 12 months, and the FF rates reported by surgeons A and B were 100% vs. 95.8%, respectively (${\kappa}=0.96$). Five out of nine facet (56%) non-unions were identified at the cross-links. The remaining four facet pseudarthrosis were noted at 1-2 spinal levels caudal to the cross-links. At the final clinical follow-up, there was no rod breakage, deformity progression, neurological deficit, or symptom recurrence. The Oswestry Disability Index improved by an average of $32.8{\pm}6.3$, while the mental component summary of the 36-item Short-Form Health Survey improved by an average of $4.7{\pm}2.1$, and physical component summary improved by an average of $10.5{\pm}2.1$. Conclusions: To our knowledge, this is the first study to report a CT that defined 92%-98% FF and 100% IBF using the lowest reported dose of RhBMP-2 in multilevel ASD surgery. The use of ultra-low dose RhBMP-2 reduces the RhBMP-2 related complications and healthcare costs.

• Journal of Veterinary Clinics
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• v.39 no.6
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• pp.302-310
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• 2022

Recently, in human medicine and veterinary medicine, interest in synthetic bone graft is increasing. Among them, bone morphogenic protein (BMP) is currently being actively researched and applied to clinical trials. However, BMP has the disadvantage of being expensive and easily absorbed into surrounding tissues. Therefore, BMP requires the use of small amounts and rhBMP (recombinant human bone morphogenetic protein)-2 carriers that can be released slowly. Hydrogel has the property of swelling a large amount of water inside when it is aqueous solution, and when it is, it consists of more than 90 percent water. Using these properties, hydrogels are often used as rhBMP-2 carrier. The scaffold used in this study is a hydrogel made from which keratin is extracted using human hair and based on it. In this study, we wanted to see the effect of bone formation in the calvarial defect model by using keratin-based hydrogel made with human hair as a scaffold. The experiment was conducted by dividing 3 groups a total of 12 mice. Calvarial bone defect is set to all 4 mm diameters. Bone formation was evaluated by using gross evaluation, micro-computed tomography (micro-CT), immunohistochemistry. Groups using keratin-based hydrogel were significantly observed compared to Group 1s, and the most bone formations were found when rhBMP-2 and hydrogel were used. This represents the superiority of the functions of the rhBMP-2 carrier by a new material, keratin-based hydrogel. Through gross evaluation, micro-CT, and immunohistochemistry, we can confirm that keratin-based hydrogel is a useful rhBMP-2 carrier.

• Journal of Korean Neurosurgical Society
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• v.64 no.4
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• pp.562-574
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• 2021

Objective : This study is to evaluate the efficacy and safety of demineralized bone matrix (DBM) gel versus DBM gel with recombinant human bone morphogenetic protein-2 (rhBMP-2) used in transforaminal lumbar interbody fusion (TLIF). Methods : This study was designed as a prospective, multi-center, double-blind method, randomized study. All randomized subjects underwent TLIF with DBM gel with rhBMP-2 group (40 patients) as an experimental group or DBM gel group (36 patients) as a control group. Post-operative observations were performed at 12, 24, and 48 weeks. The spinal fusion rate on computed tomography scans and X-rays films, Visual analog scale pain scores, Oswestry disability index and SF-36 quality of life (QOL) scores were used for the efficacy evaluation. The incidence rate of adverse device effects (ADEs) and serious adverse device effects (SADEs) were used for safety evaluation. Results : The spinal fusion rate at 12 weeks for the DBM gel with rhBMP-2 group was higher with 73.68% compared to 58.82% for the DBM gel group. The 24 and 48 weeks were 72.22% and 82.86% for the DBM gel with rhBMP-2 group and 78.79% and 78.13%, respectively, for the DBM gel group. However, there were no significant differences between two groups in the spinal fusion rate at 12, 24, and 48 weeks post-treatment (p=0.1817, p=0.5272, p=0.6247). There was no significant difference between the two groups in the incidence rate of ADEs (p=0.3836). For ADEs in the experimental group, 'Pyrexia' (5.00%) was the most common ADE, followed by 'Hypesthesia', 'Paresthesia', 'Transient peripheral paralysis', 'Spondylitis' and 'Insomnia' (2.50%, respectively). ADEs reported in control group included 'Pyrexia', 'Chest discomfort', 'Pain', 'Osteoarthritis', 'Nephropathy toxic', 'Neurogenic bladder', 'Liver function analyses' and 'Urticaria' (2.86%, respectively). There was no significant difference between the two groups in the incidence rate of SADEs (p=0.6594). For SADE in the experimental group, ''Pyrexia' and 'Spondylitis' were 2.50%. SADE reported in the control group included 'Chest discomfort', 'Osteoarthritis' and 'Neurogenic bladder'. All SADEs described above were resolved after medical treatment. Conclusion : This study demonstrated that the spinal fusion rates of DBM gel group and DBM gel with rhBMP-2 group were not significantly different. But, this study provides knowledge regarding the earlier postoperative effect of rhBMP-2 containing DBM gel and also supports the idea that the longer term follow-up results are essential to confirm the safety and effectiveness.

• Molecules and Cells
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• v.39 no.5
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• pp.389-394
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• 2016

Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.