• Asian Pacific Journal of Cancer Prevention
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• 제14권9호
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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.

• BMB Reports
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• 제44권10호
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• pp.619-634
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• 2011

Bone morphogenetic protein (BMP) signaling in diseases is the subject of an overwhelming array of studies. BMPs are excellent targets for treatment of various clinical disorders. Several BMPs have already been shown to be clinically beneficial in the treatment of a variety of conditions, including BMP-2 and BMP-7 that have been approved for clinical application in nonunion bone fractures and spinal fusions. With the use of BMPs increasingly accepted in spinal fusion surgeries, other therapeutic approaches targeting BMP signaling are emerging beyond applications to skeletal disorders. These approaches can further utilize next-generation therapeutic tools such as engineered BMPs and ex vivo-conditioned cell therapies. In this review, we focused to provide insights into such clinical potentials of BMPs in metabolic and vascular diseases, and in cancer.

• Nutrition Research and Practice
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• 제11권3호
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• pp.190-197
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• 2017

BACKGROUND/OBJECTIVES: Gallus gallus domesticus (GD) is a natural mutant breed of chicken in Korea with an atypical characterization of melanin in its tissue. This study investigated the effects of melanin extracts of GD on osteoblast differentiation and inhibition of osteoclast formation. MATERIALS/METHODS: The effects of the melanin extract of GD on human osteoblast MG-63 cell differentiation were examined by evaluating cell viability, osteoblast differentiation, and expression of osteoblast-specific transcription factors such as bone morphogenetic protein 2 (BMP-2), small mothers against decapentaplegic homologs 5 (SMAD5), runt-related transcription factor 2 (RUNX2), osteocalcin and type 1 collagen (COL-1) by reverse transcription-polymerase chain reaction and western blotting analysis. We investigated the inhibitory effect of melanin on the osteoclasts formation through tartrate-resistant acid phosphatase (TRAP) activity and TRAP stains in Raw 264.7 cell. RESULTS: The melanin extract of GD was not cytotoxic to MG-63 cells at concentrations of $50-250{\mu}g/mL$. Alkaline phosphatase (ALP) activity and bone mineralization of melanin extract-treated cells increased in a dose-dependent manner from 50 to $250{\mu}g/mL$ and were 149% and 129% at $250{\mu}g/mL$ concentration, respectively (P < 0.05). The levels of BMP-2, osteocalcin, and COL-1 gene expression were significantly upregulated by 1.72-, 4.44-, and 2.12-fold in melanin-treated cells than in the control cells (P < 0.05). The levels of RUNX2 and SMAD5 proteins were higher in melanin-treated cells than in control vehicle-treated cells. The melanin extract attenuated the formation of receptor activator of nuclear factor kappa-B ligand-induced TRAP-positive multinucleated RAW 264.7 cells by 22%, and was 77% cytotoxic to RAW 264.7 macrophages at a concentration of $500{\mu}g/mL$. CONCLUSIONS: This study provides evidence that the melanin extract promoted osteoblast differentiation by activating BMP/SMADs/RUNX2 signaling and regulating transcription of osteogenic genes such as ALP, type I collagen, and osteocalcin. These results suggest that the effective osteoblastic differentiation induced by melanin extract from GD makes it potentially useful in maintaining bone health.

• IMMUNE NETWORK
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• 제23권6호
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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.

• 대한치과의사협회지
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• 제52권4호
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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.

• Biomolecules & Therapeutics
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• 제19권1호
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• pp.70-76
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• 2011

Bone remodeling is a dynamic process involving a constant balance between osteoclast-induced bone resorption and osteoblast-induced bone formation. Osteoclasts play a crucial homeostatic role in skeletal modeling and remodeling, and destroy bone in many pathological conditions. Previously, we reported that the hexane soluble fraction of Ficus carica inhibited osteoclast differentiation. Poly unsaturated fatty acids, such as ethyl docosahexaenoate (E-DHA), docosahexaenoic acid (DHA), cis-11,14-eicosadienoic acid (EDA) and eicosapentaenoic acid (EPA), were identified from the hexane soluble fraction of Ficus carica. Among them, E-DHA most potently inhibited osteoclastogenesis in RAW264.7 cells. E-DHA reduced the activities of JNK and NF-$\kappa}B$. E-DHA suppressed the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1). Interestingly, DHA increased the activity of alkaline phosphatase and expression of bone morphogenetic protein 2 (BMP2) more than E-DHA in MC3T3-E1 cells, suggesting that DHA may induce osteoblast differentiation. The data suggests that a combination of E-DHA and DHA has potential use in the treatment of diseases involving abnormal bone lysis, such as osteoporosis, rheumatoid arthritis and periodontal bone erosion.

• Molecules and Cells
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• 제39권5호
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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.

• 대한치과보철학회지
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• 제51권4호
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• pp.307-314
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• 2013

연구 목적: 본 연구는 골형성단백질의 서방출을 위해 헤파린과 골형성단백질 (rhBMP-2)을 화학적으로 고정시킨 양극산화 티타늄 임플란트가 골 결손부에서 임플란트 주변의 수직적 골증대에 미치는 효과를 방사선학적으로 평가하고자 시행되었다. 연구 재료 및 방법: Pure-Titanium을 사용하여 길이 7.0 mm, 직경 3.5 mm의 실험용 임플란트 18개를 제작하였다. 모든 임플란트를 양극산화처리 하였고, 플랫폼 하방 2.5 mm에 식립 기준선을 표시하였다. rhBMP-2가 코팅되지 않은 임플란트 집단을 대조군으로, dip and dry 방법으로 rhBMP-2를 물리적 흡착시킨 집단을 BMP군, 3,4-dihydroxyphenylalanine(DOPA)-heparin을 이식하고 rhBMP-2를 화학적으로 고정시킨 집단을 Hep-BMP군으로 설정하였다. 각군별6개씩의 임플란트를 3마리의 비글견 양측 하악에 한쪽에 3개씩 총 18개를 치조정 상방으로 2.5 mm 노출시켜 식립하였다. 식립 직후와 4주, 8주에 식립부위의 방사선학적 검사가 시행되었고, 각 시기별, 각 군별 임플란트의 근원심 변연골의 수직적 재생량에 대한 평균값과 표준편차를 얻었다. Kruskal-Wallis test와 Mann-Whitney U test를 이용하여 4주, 8주에서 대조군과 실험군들의 차이를 비교 분석하고, 유의 수준5%에서 통계적으로 검정하였다. 결과:방사선학적 관찰 결과 임플란트 근원심 변연골 재생량(평균값 ${\pm}$ 표준편차)은 4주에 대조군은 $0.09{\pm}0.22mm$, BMP군은 $1.02{\pm}0.72mm$, Hep-BMP군은 $1.29{\pm}0.51mm$ 였으며, 8주에서는 각각 $0.11{\pm}1.26mm$, $1.11{\pm}0.58mm$, $1.59{\pm}0.79mm$였다. 두 실험군 모두 4주와 8주에서 대조군과 비교 시 유의한 수직적 골증대를 나타냈으나(P<.05), Hep-BMP군과BMP군의 비교에서는 유의한 변연골 재생량 차이를 보이지 않았다(P>.05). 결론: 골형성단백질을 물리적으로 흡착시키거나 서방출 위해 헤파린을 이용하여 화학적으로 고정시킨 양극산화 임플란트 표면은 모두 골 결손부에서 임플란트 주변골의 수직적 증대에 효과적이었다. 그러나 방사선학적 관찰의 한계 내에서 골형성단백질의 이 두가지 적용방법간에는 수직적 골증대량에 유의한 차이가 없었다.

• 한국임상수의학회지
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• 제15권2호
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• pp.442-449
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• 1998

Freeze-dried cortical bones of the goat were transplanted to the experimental fibular defect of 10 dogs for valuating the possibility of xenogeneic bone implantation and the specificity of BM(Bone Morphogenetic Protein). The . freeze-dried cortical bone eliminated antigens and defatted with chloroform and methanol were freeze-dried at $-80{\circ}C$ for preservation of BMP and then sterilized with 50 gas and storaged in room temperature. Ten freeze-dried cortical implants of the goat were transplanted in experimentally defected regions of bilateral fibula of 5 dogs in clinically normal. The transplanted region had been radiographed for observing state of bone union and BALPOone Alkaline Phosphatase) in the serum of the host was measured for valuating activity of oteoblast per 2 week-interval after transplant procedures. New bone formation had been observed early in one of ten regions around implants about the same time as autoimplant regions. It was incorporated with its host bone during 4-12 weeks after transplantation. In another 2 cases of 2 dogs, new bone formation and absorption of implant had been observed from 4 weeks but they were not incorporated completely until 20 weeks. The rest of the freeze-dried bone implants, 7 cases of 4 dogs had not been observed new bone formation nor absorption of implants. The freeze-drying method for implants means to not influence bone incorporation. Although less of union percentages the union form of this experiment were similar to alloimplantation and it may mean to block immunity reaction that disturbs the bone induction by BMP. It demonsknted that the possibility of the xenogenous bone implantation is recognized by reason of the low specificity of BMP between goat and dog.

• Journal of Periodontal and Implant Science
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• 제46권4호
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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.