Tratamiento farmacológico del estrabismo / Pharmacological treatment of strabismus

La cirugía de la musculatura extraocular ha sido el estándar de atención para tratamiento quirúrgico del estrabismo por más de un siglo. A pesar del gran desarrollo técnico de la cirugía de estrabismo en la actualidad, la utilización de microscopio quirúrgico, el diseño novedoso del instrumental quirúrgico, la calidad de la sutura no reabsorbible; los avances en equipamiento y fármacos anestésicos, la misma no está exenta de complicaciones quirúrgicas, además del tiempo de recuperación que necesita el paciente para reincorporarse a sus actividades sociales, han propiciado una búsqueda permanente del tratamiento farmacológico para el estrabismo. El objetivo de esta revisión bibliográfica es analizar las distintas alternativas farmacológicas disponibles como tratamiento del estrabismo. Para su confección se consultó textos completos y artículos en idiomas español e inglés, disponible en algunas bases de datos. Concluimos que aunque se han estudiado numerosos fármacos, la toxina botulínica que es la más conocida y utilizada mundialmente, seguida de la bupivacaína. Encontramos otros como la IGF I y II (Insuline Growing Factor), capaces de generar un efecto de reforzamiento de la actividad muscular. Y otros que "debilitan" la musculatura extraocular, incluyen la mAb35-Rubicina, BMP4 (Proteína morfogénica ósea). Se continúa su investigación en la actualidad(AU)

Extraocular musculature surgery has been the standard of care for surgical treatment of strabismus for more than a century. Despite the great technical development of strabismus surgery today, the use of a surgical microscope, the novel design of surgical instruments, the quality of the non-absorbable suture; Advances in anesthetic equipment and drugs, it is not exempt from surgical complications, in addition to the recovery time that the patient needs to return to their social activities, have led to a permanent search for pharmacological treatment for strabismus. The objective of this bibliographic review is to analyze the different pharmacological alternatives available as a treatment for strabismus. For its preparation, full texts and articles in Spanish and English languages were consulted, available in some databases. We conclude that although numerous drugs have been studied, botulinum toxin, which is the best known and used worldwide, followed by bupivacaine. We find others such as IGF I and II (Insuline Growing Factor), capable of generating an effect of reinforcing muscle activity. And others that "weaken" MOE include mAb35-Rubicin, BMP4 (Bone Morphogenic Protein). His research is continuing today(AU)

BMP4 Induces Cardiomyocyte Hypertrophy Through the Activation of ERK 1/2 Signaling Pathway in H9c2 Cells

Abstract Bone morphogenetic protein-4 (BMP4) is a member of the bone morphogenetic protein family which plays an important role in bone formation, inflammation and cardiac hypertrophy. The aim of this study was to investigate the underlying molecular mechanism that BMP4-induced cardiomyocyte hypertrophy. H9c2 cells were used to measure cell surface area and protein synthesis. Western blot was used to examine hypertrophic marker brain natriuretic peptide (BNP) protein expression and phosphorylation of ERK1/2. The results exhibited that cell surface area, protein synthesis and BNP protein expression were increased with BMP4 treatment. While PD98059 inhibited these effects of BMP4. In addition, BMP4 treatment increased phosphorylation of ERK1/2 in a time- and dose-dependent manner. PD98059 treatment decreased phosphorylation of ERK1/2 that was increased by BMP4. These results suggest that BMP4 induces cardiomyocyte hypertrophy through the activation of ERK1/2 cell signaling pathway.

Association of single nucleotide polymorphisms in AXIN2, BMP4, and IRF6 with Non-Syndromic Cleft Lip with or without Cleft Palate in a sample of the southeast Iranian population

Abstract Non-syndromic cleft lip with or without palate (NSCL/P) is a common congenital malformation worldwide, with complex etiology. It has been proposed that interaction of genes and environmental factors play a role in the predisposition to this disease. Objectives: The aim of this study was to examine the association between AXIN2 (axis inhibition protein 2) rs7224837, BMP4 (bone morphogenetic protein 4) rs17563, and IRF6 (interferon regulatory factor 6) rs861019 and 2235371 polymorphisms and NSCL/P in an Iranian population. Material and Methods: This case-control study was carried out on 132 unrelated NSCL/P patients and 156 healthy subjects. The variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The findings suggest that BMP4 rs17563 polymorphism significantly decreased the risk of NSCL/P in codominant (OR=0.36, 95%CI=0.17-0.79, p=0.012, CT vs CC and OR=0.11, 95%CI=0.01-0.88, p = 0.019, TT vs CC), dominant (OR=0.30, 95%CI=0.15-0.62, p = 0.0007, CT+TT vs CC), recessive (OR=0.12, 95%CI=0.02-0.99, p = 0.023, TT vs CC+CT), overdominant (OR=0.39, 95%CI = 0.18-0.84, p=0.021, CT vs CC+TT), and allele (OR=0.28, 95%CI=0.15-0.55, p<0.0001, T vs C) inheritance models. Our findings did not support an association between AXIN2 rs7224837 and IRF6 rs861019 polymorphism and risk/protection of NSCL/P. The IRF6 2235371 variant was not polymorphic in our population. Conclusion: The results indicate that the BMP4 rs17563 variant is likely to confer a protective effect against the occurrence of NSCL/P in a sample of the southeast Iranian population.

Regulations of berberine on gene expression of BMP4 transcriptional pathways to improve visceral white adipose tissues insulin resistance in type 2 diabetic hamsters / 中国中药杂志

To study the effects of berberine on the gene mRNA expressions of BMP4 transcriptional pathways and brown/white adipose tissue conversion transcriptional pathways in visceral white adipose tissues(VWAT) in type 2 diabetic hamsters and explore the relevant mechanisms. The obese insulin-resistant hamster model were induced by using high-fat diet, and then the type 2 diabetic hamster model was created through injection with low-dose streptozotocin in the obese insulin-resistant hamster model. After the modeling, the hamsters were randomly divided into normal control, obese insulin-resistant, type 2 diabetic and berberine-treated diabetic groups. After the nine-week treatment, real-time quantitative PCR was used to measure the changes in gene mRNA expressions of VWAT BMP4 transcriptional pathways, brown/white adipose tissue conversion transcriptional pathways and their target genes in different groups. The results showed that the gene mRNA expressions of BMP4, BMPRⅡ, BMPRlA, Smad1, Smad5, Smad8, p38/MAPK, ATF2, PRDM16, C/EBPβ, PGC1α, PPARγ and brown adipose tissue-specific genes was decreased and that of Smad6, Smurf1 and white adipose tissue-specific genes was increased in VWAT of model hamsters. Treatment with berberine regulated BMP4 transcriptional pathways and brown adipose tissue transcriptional pathways and induced the gene mRNA expression of brown adipose tissue-specific genes in VWAT to develop browning gene phenotype of white adipose tissues, and then improved fat-induced insulin resistance. These findings indicated that BMP4 transcriptional pathways involved in the formation of fat-induced visceral white adipose tissues insulin resistance (FIVWATIR) and the browning molecular mechanism of white adipose tissues induced by berberine.

BMP4 promotes migration and invasion of hepatocellular carcinoma by inducing epithelial-mesenchymal transition / 中国肿瘤临床

Objective:To determine the expression of BMP4 in hepatocellular carcinoma (HCC) and to study the role of BMP4 in inducing epithelial-mesenchymal transition (EMT) to analyze the effect of BMP4 on the migration and invasion of HCC cells. Methods: The expression of BMP4 in HCC specimens was examined by immunohistochemistry staining, and the correlations were analyzed between the expression of BMP4 and clinicopathological data. The BMP4 expression plasmid was transfected into HepG2 cells to induce exogenous overexpression of BMP4 protein. The changes of HepG2 cell morphology were detected after BMP4 transfection by using a microscope; the changes of the expression of BMP4, EMT-related protein (E-cadherin, Vimentin) in HepG2 cells were detected by Western blot after transfection of BMP4;the wound healing assay in vitro was used to detect the effects of BMP4 gene transfection on the ability of migration of HepG2 cells;the invasion assay was used to determine the role of transfection of BMP4 on the invasive potential of HepG2 cells. Results: Immunohistochemistry staining method displayed that BMP4 expression was positively associated with age, histological differentiation, stage, and poor prognosis. After BMP4 overexpression, the morphology of HepG2 cells showed significant changes from a paving stone structure with cell-cell adhesion to a fibroblastic shape, which showed typical EMT change; Western blot exhibited that the expression of E-cadherin was downregulated and the Vimentin expression was upregulated in HepG2 cells;the wound healing and invasion assay showed that the migration and invasion potentials of HepG2 cells were significantly enhanced. Conclusion: BMP4, which displayed a high expression in HCC specimens, was closely associated with clinicopathologic data, and BMP4 may promote migration and invasion of HCC cells by inducing epithelial-mesenchymal transition.

Expression and its correlations of caudal type homeobox transcription factor-2, heparin-binding epidermal growth factor-like growth factor and bone morphogenetic protein-4 in Barrett's esophagus / 中华消化杂志

Objective To explore the function and significance of caudal type homeobox transcription factor-2 (CDX)-2,heparin-binding epidermal growth factor-like growth factor (HB-EGF) and bone morphogenetic protein 4 (BMP-4) of esophageal stromal tissues in the pathogenesis of Barrett's esophagus (BE).Methods A total of 116 patients were divided into groups according to gastroscopic finds and hematoxylin-eosin (H &E) staining of biopsy samples.They were divided into control group (n=29),RE group (n=32),BE group (n=35),RE treatment group (n=10) and BE treatment group (n=10).The expression of CDX 2,HB-EGF and BMP-4 in different esophageal mucosal lesions was detected by immunohistochemical staining and the changes of positive expression levels of CDX-2,HBEGF and BMP 4 were compared among groups.Variance analysis and chi-square analysis were performed to analyze the correlation among the three factors.Results The CDX-2 positive cell number of control group ((0.0±0.0)/high power field(HPF)),RE group ((43.1±10.6)/HPF),and BE group ((67.8±11.3)/HPF) increased in turn,and the differences among three groups were statistically significant (F=67.664,P＜0.01).The HBEGF positive ((6.4±1.4)/HPF,(39.4±13.5)/HPF,(55.8±13.9)/HPF) and BMP 4 positive ((0.0±0.0)/HPF,(22.6±6.4)/HPF and ((25.1± 10.3)/HPF) cell number of three groups had the same trend and the differences among three groups were statistically significant (F HB-EGF =22.925,FBMP-4 =10.463,both P＜0.01).Except the expression of BMP-4 between RE group and BE group,there were significant differences between every other two groups (LSD test,all P＜ 0.01).The expression of CDX 2,HB EGF,BMP-4 in RE treatment group ((21.7±1.7)/HPF,(16.6±5.0)/HPF and (9.2±1.0)/HPF) and BE treatment group ((51.4±8.7)/HPF,(31.0± 10.4)/HPF and (12.7±3.9)/HPF) were lower than those in RE group and BE group respectively,the differences were also statistically significant (LSD test,all P＜0.05).In RE group,the positive rate of CDX-2 (31.2％ (10/32)) was significantly lower than that of HBEGF and BMP4 (62.5％ (20/32) and 56.2％(18/32)),and the differences were statistically significant (x2=6.275 and 4.063,both P＜0.05).However in BE group,there was no statistically significant difference in the positive rate among CDX-2(85.7％(30/35)),HB-EGF (88.6％(31/35)) and BMP-4 (74.3％(26/35),all P＞0.05).Conclusions CDX-2,HB-EGF and BMP-4 may play an important role in the pathogenesis of RE and BE.HB-EGF and BMP-4 may be involved in the early episodes of BE genesis and have promotion effects on CDX-2 expression.HB-EGF and BMP-4 may be the new target in the research and treatment of BE.

Bimaxillary orthognathic surgery and condylectomy for mandibular condyle osteochondroma: a case report / 대한악안면성형재건외과학회지

Osteochondroma is rarely reported in the maxillofacial region; however, it is prevalent in the mandibular condyle. This slowly growing tumor may lead to malocclusion and facial asymmetry. A 39-year-old woman complained of gradual development of anterior and posterior unilateral crossbite, which resulted in facial asymmetry. A radiological study disclosed a large tumor mass on the top of the left mandibular condyle. This bony tumor was surgically removed through condylectomy and the remaining condyle head was secured. Subsequently, bimaxillary orthognathic surgery was performed to correct facial asymmetry and malocclusion. Pathological diagnosis was osteochondroma; immunohistochemistry showed that the tumor exhibited a conspicuous expression of BMP-4 and BMP-2 but rarely expression of PCNA. There was no recurrence at least for 1 year after the operation. Patient's functional and esthetic rehabilitation was uneventful.

Study of the association between the BMP4 gene and congenital anomalies of the kidney and urinary tract / Estudo da associação entre o gene BMP-4 e anomalias congênitas do rim e trato urinário

OBJECTIVE: To determine the frequency of different phenotypes for congenital anomalies of the kidney and urinary tract (CAKUT) in a Brazilian sample, and to evaluate the association between the CAKUT phenotypes and the BMP4 gene. METHODS: In this study, 457 Brazilian individuals were analyzed in an attempt to establish the association between the BMP4 gene and the CAKUT diagnosis. A case-control sample was genotyped for three BMP4 gene polymorphisms. RESULTS: Association data was established with CAKUT sample as a whole and with the three most important CAKUT phenotypes: multicystic dysplastic kidney disease (MDK), ureteropelvic junction obstruction (UPJO) and vesicoureteral reflux (VUR). When the sample was segregated in these three phenotypes, associations between the BMP4 gene were observed with UPJO and with MDK. Conversely, VUR was not associated to the polymorphisms of the BMP4 gene. CONCLUSIONS: The present data suggest that Brazilian individuals with polymorphisms of the BMP4 gene have a higher risk to develop CAKUT, especially the malformations related to nephrogenesis and initial branching such as MDK and UPJO. Conversely, VUR appeared not to be related to BMP4 gene. .

OBJETIVO: Determinar a frequência de diferentes fenótipos de anomalias congênitas do rim e trato urinário (CAKUT) em uma amostra brasileira e avaliar a associação entre os CAKUT e o gene BMP-4. MÉTODOS: Neste estudo, analisamos 457 indivíduos brasileiros em uma tentativa de estabelecera associação entre o gene BMP-4 e o diagnóstico de CAKUT. As amostras de caso e de controle foram genotipadas em busca de três polimorfismos do gene BMP-4. RESULTADOS: Os dados de associação foram estabelecidos com a amostra de CAKUT como um todo e com os três fenótipos de CAKUT mais importantes: rim displásico multicístico (RDM), obstrução da junção ureteropélvica (UPJO) e refluxo vesico-ureteral (VUR). Quando a amostra foi separada nesses três fenótipos, encontramos associações entre o gene BMP-4 com UPJO e com RDM. Por outro lado, o VUR não foi associado aos polimorfismos do gene BMP-4. CONCLUSÕES: Esses dados sugerem que os indivíduos brasileiros com polimorfismos do gene BMP-4 apresentam maior risco de desenvolver CAKUT, principalmente as malformações relacionadas a nefrogênese e ramificação inicial, como RDM e UPJO. Por outro lado, o VUR parece não estar relacionado ao gene BMP-4. .

Immunohistochemical detection of BMP-2 and BMP-4 in the developing neural tube and spinal cord of human embryos / Detección inmunohistoquímica de BMP-2 y BMP-4 en el desarrollo del tubo neural y médula espinal del embrión humano

The role of bone morphogenetic proteins (BMP-s) in the development of the nervous system has been widely studied on avian and rodent embryos. Human embryos have rarely been available for detection of BMP expression. In this study 39 human embryos of Carnegie stages (CS) 10-20 were investigated. The embryos were fixed in paraformaldehyde, embedded in paraffin and sectioned serially in transverse direction. BMP-2 and BMP-4 protein expression in the developing neural tube and the caudal spinal cord was determined by immunohistochemistry. Our data show that BMP-s tend to be more expressed in the neural tube in earlier stages; in particular, BMP-4 staining was found to be higher at CS10 compared to CS20. More detailed analysis was performed on embryos of CS14-18. Stronger BMP-2 and BMP-4 expression was found in the dorsal part than in the ventral part of the spinal cord. No differences were seen in the staining intensity of BMP-s in the spinal ganglia. Interestingly, in neural crest cells BMP-2 staining was stronger at CS16 and CS18 as compared to CS14, while no differences were found in BMP-4 staining. On the other hand, in the non-neural ectoderm BMP-4 staining was found to be stronger at CS16 than at CS14, while no differences were seen for BMP-2. In conclusion, expression of BMP-s in the developing neural tube and spinal cord of human embryos is generally in accordance with the findings made in rodents and birds.

El papel de las proteínas morfogenéticas óseas (BMP-s) ha sido ampliamente estudiado en el desarrollo del sistema nervioso en embriones de aves y roedores. Los embriones humanos rara vez han estado disponibles para la detección de la expresión de BMP. En este estudio se investigaron 39 embriones humanos de los estadios Carnegie (CS) 10-20. Los embriones fueron fijados en paraformaldehído, embebidos en parafina y seccionados en serie en dirección transversal. Se determinó por inmunohistoquímica BMP-2 la expresión de la proteína BMP-4 en el tubo neural y en la médula espinal caudal en desarrollo. Nuestros resultados mostraron que la BMP-s tienden a ser más expresadas en el tubo neural en etapas tempranas, en particular, se encontró tinción BMP-4 más alta en comparación con CS10 CS20. Un análisis más detallado se realizó en embriones de CS14-18. En la parte dorsal se observó mayor expresión de BMP-2 y de BMP-4 que en la parte ventral de la médula espinal. No se observaron diferencias en la intensidad de la tinción de BMP-s en los ganglios espinales. Curiosamente, en las células de la cresta neural BMP-2 la tinción fue más fuerte en CS16 y CS18 en comparación con CS14, mientras que no se encontraron diferencias en la tinción de BMP-4. Por otro lado, en el ectodermo no neural se encontró tinción BMP-4 más fuerte en CS16 que en CS14, mientras que no se observaron diferencias para BMP-2. En conclusión, la expresión de BMP-s en el tubo neural en desarrollo y la médula espinal de embriones humanos está generalmente de acuerdo con los hallazgos realizados en roedores y aves.

BMP4 promote chondrogenic differentiation of human periosteum-derived cells in vitro / 中华显微外科杂志

Objective To explore biological characteristics of chondrogenic differentiation of human periosteum-derived cells and the role of BMP4 in chondrogenic differentiation of these cells.Methods From October 2009 to September 2012,periosteum was obtained from tibia of patients undergoing leg amputation surgery,and isolated periosteum-derived cells by tissue culture method.Cells were cultured in DMEM/F12 containing 10％ fetal bovine serum,and morphology of cells were observed under inverted microscope.Periosteum-derived cells growth and the effect of BMP4 on cells growth examined by cell count using trypan blue,and cells growth curve was made.Experiment was divided into control group,chondrogenic differentiation group and BMP4 group,cells were expanded and differentiated in the presence or absence of BMP4 and complete medium.Then toluidine and immunohistochemical staining analyzed proteoglycan and collagenⅡ expression of these cells after 14 and 21 days.The expression of aggrecan,collagen Ⅱ and SOX9 mRNA of these cells using real-time PCR.Results (1) Periosteumderived cells adhered to growth in vitro,the shape of cell presented fibroblast-like morphology changing into polygonal after 1 week and round cell formation after 2 weeks chondrrogenic differemtiation.Growth curve showed that the passage 3 and 9 cells had similar reproductive activity.The passage 3 cells were positive for CD90 (21.07％) and CD105 (25.84％).(2)Toluidine bule staining and type Ⅱ collagen immunohistochemical staining showed BMP4 group (40.29 ± 4.29,56.74 ± 5.12) and chondrogenic differentiated group (19.27 ± 3.71,38.31 ± 4.25) ccould secrete proteoglycan and collagen Ⅱ,control group were negative (10.24 ± 1.21,15.28 ± 2.23),BMP4 group were significantly than chondrogenic differentiated group.(3) The expression of aggrecan,collagen Ⅱ and SOX9 mRNA of BMP4 group(25.76 ±0.57,6.48 ±0.48,2.91 ±0.18)were significantly higher than that of control group(2.37 ±0.24,1.12 ± 0.31,1.07 ± 0.22)and chondrogenic differentiated group(11.12 ± 0.38,2.24 ± 0.41,1.54 ± 0.35)using real-time PCR.Conclusion Periosteum-derived cells have strong proliferative,and have good potentials of differentiating into chondroblasts like mesenchymal stem cells.BMP4 can promote chondrogenic differentiation of periosteum-derived cells in vitro cultures.

The Effects of Hyperthermia on FGF-8 and BMP-4 Expression during Early Odontogenesis in Hsp70 Knock-out Mice Fetuses / 체질인류학회지

During early tooth development, multiple signaling molecules are expressed in the dental lamina and induce the dental mesenchyme. One signal, FGF-8, is expressed in the early dental epithelium, another one, BMP-4, has been shown to induce morphologic changes in dental mesenchyme. Meanwhile, hyperthermic exposure during pregnancy, as one of teratogens, is known to disturbe normal development and induce several congenital anomalies. This study is aimed to investigate the effects of maternal hyperthermia on the expressions of FGF-8 and BMP-4 in early odontogenesis. The pregnant Hsp70 knock-out at gestational day 8 were immersed in 43degrees C water bath until their body core temperature reached at 43degrees C. Thereafter, pregnant mice were given more 5 minutes hyperthermic exposure. Heat-untreated Hsp70 KO mice fetuses were used as the control group. Fetuses were collected at embryonic day (ED) 13, 15 and 17. Developing tooth in the mandible was processed for immunohistochemical study. Tissue sections were immunostained for FGF-8 and BMP-4 and observed with light microscope. The obtained results were as follows: Tooth development in the heat shocked (HS) group is delayed rather than the control group in the given developmental period. FGF-8 immunolocalization in control group at ED 13 was gradually decreased compared to the HS group which showed continuously positive immunoreaction. BMP-4 immunolocalization was detected in dental mesenchyme, however, there was no positive immunoreaction found in HS group. These results suggest that maternal hyperthermia should induce the early odontogenesis, delay the expression of FGF-8 in dental epithelium, and disturbe the expression of BMP-4 in dental mesenchyme. Consequently, hyperthermic exposure during pregnancy affects epithelial-mesenchymal interactions.

Expression of BMP4, BMP6 following sinus elevation with DBBP in rabbit

0.05). 2. The expression of BMP6 increased at postoperative 1 and 3 days in both DBBP group and AGS group. In AGS group, it decreased at postoperative 5 days, increased again at postoperative 7 days, and decreased at postoperative 9 days. In DBBP group, it increased until postoperative 7 days and decreased at postoperative 9 days. Although the expression of BMP6 was higher in AGS group compared with DBBP group, it was not statistically significant (p>0.05). 3. There was no statistically significant difference in BMP expression in both groups during same period of time. It's probably because DBBP and AGS both functioned as a space retainer so that the BMP expression in blood clot seemed to be similar. 4. Thus, DBBP would not offer many benefits for early bone regeneration compared with AGS. The expression of BMP in early bone formation seems to be more influenced by physical carrier rather than the graft type.

Synergistic Effect of Isoflavones on the BMP-4 MediatedOsteoblastic Differentiation of C2C12 Myoblast / 대한정형외과학회잡지

PURPOSE: Isoflavones are rich in soybean and are known to affect bone formation. This study examined the effects and modes of action of isoflavones on the differentiation of C2C12 myoblasts in the presence of the bone morphogenetic protein (BMP)-4. MATERIALS AND METHODS: The isoflavones, daidzein, genistein or equol, and/or BMP-4 were added alone or in combination to C2C12 myoblasts. After 72 hours culture, the cells were stained for the early osteoblastic differentiation marker, alkaline phosphatase (ALP). The ALP activity was determined by comparing the color of the stained images as well as by spectrophotometry. The expression profiles of the extracellular matrix (ECM) genes responsible for the extensive remodeling at the cell surface were analyzed using agene expression microarray after treating thesamples with daidzein. RESULTS: ALP staining of BMP-4 or the isoflavones-treated cells showed that BMP-4 increased the activity of ALP in a dose dependent manner, whereas the isoflavones alone did not induced any remarkable increase. However, the ALP activity increased when the cells were treated with BMP-4 and any of the three isoflavones. The macrogen mouse MAC array data showed that the ECM genes, Mmp13 and Mmp3, were up-regulated by daidzein, whereas Col4a2, Col5a1 and Mmp9 were down-regulated. CONCLUSION: Isoflavones induce osteoblastic differentiation when combined with BMP-4, which is possibly achieved by modulating the expressional levels of various ECM genes.

Expression of TGF-beta 1, osteonectin and BMP-4 on bone regeneration in mandibular distraction osteogenesis combination with a compression stimulation

Distraction osteogenesis(DO) is a technique of lengthning bone including soft tissue by gradual separation of surgically divided bone surfaces. Distraction osteogenesis combination with a compression stimulation(DO-CO) was a new technique by authors to enhance new bone quality and to shorten the consolidation period. The purpose of this study was to compare DO with DO combined with compression force in efficiency by evaluating the expression of TGF-beta 1, osteonectin and BMP-4 on bone regenerate in rabbit mandible. Fourty two rabbits were used for this experiment. On the control group, the distraction was carried out at the rate of 1 mm per day to obtain the amount of 8 mm distraction for 8 days. On the experimental group, the distraction was carried out at the rate of 1 mm per day for 10 days, 3 days-latency period, and then the compression was carried out as counter direction 1 mm per day for 2 days. After 0 day, 5 days, 13 days, 20 days, 27 days, 34 days and 41 days, three rabbits on each group were sacrificed and the distracted portion of mandible were cut and treated for RT-PCR observation. The level of expression of TGF-beta 1 and osteonectin were shown more and longer expression in the experimental group than in the control group. The expression of BMP-4 was maintained with high level during the entire experimental period in both groups. These findings suggested that DO with compression stimulation could be a favorable technique for obtaining a good new bone quality.

Expression of osseointegration-related genes around titanium implant: BMP2, BMP4

The effects of BMP4 and BMP2 on Expression of Trophoblast-Specific Genes in Human Embryonic Stem Cells using SNU-hES3 cell line / 대한산부인과학회지

OBJECTIVE: Human embryonic stem cell derived from blastocyst randomly differentiates into multiple cell types during embryoid body development. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor type beta superfamily. We have a question whether BMP2 and/or BMP4 can induce trophoblast specific genes in human ES cells using SNU hES3 cell line. METHODS: Human embryonic stem cell line (SNU hES3) was supplied by Miz Medi Hospital Seoul National University. Cultured hES cells were divided into small clumps and then allow for EB formation in differentiation medium. After EB formation, EBs were transferred onto gelatin coated dishes and given hES conditioned medium alone (control) or supplemented as following treatment for 6 days; rhBMP4 100 ng/mL; rhBMP2 100 ng/mL; BMP4 100 ng/mL +BMP2 100 ng/mL. RT PCR was performed for trophoblast specific genes. During culture, supernatant was collected and measured for estradiol (E2), progesterone, and hCG beta by enzymeimmuno assay (EIA) kit. RESULTS: BMP4 and BMP2 increase chorionic gonadotropin beta (hCG beta), glical cell missing 1 (GMC1), and CD9 as trophoblast specific gene markers confirmed by RT PCR. However, the non classical HLA class I molecule HLAG1, was not expressed in our studies. And we cannot find significant differences of the level of estradiol, hCG nd progesterone in this study. CONCLUSION: The results suggest that BMP 4 and 2 have an additive effect on induction of trophoblast related genes in SNU hES3 cell line. Although we failed to induce the differentiation of human ES cells to trophoblast, this study could provide the possibility for the differentiation of early human trophoblast cells and thus need further studies.

Expression of BMP-2, -4 during distraction osteogenesis in the rabbit mandible

Distraction osteogenesis(DO) is defined as a gradual mechanical process of mechanical stretching two vascularized bone surface apart with a critical rate and rhythm such that new bone forms within the expanding gap, reliably bridges the gap, and ultimately remodels to normal structure. DO has become a mainstay in bone tissue engineering and has significantly improved our armamentarium for reconstructive craniomaxillofacial procedures. But the molecular and biological mechanisms that regulate the formation of new bone during distraction osteogenesis are not completely understood. BMPs are potent osteoinductive agents. Our hypothesis was that BMPs, especially BMP-2 and BMP-4, might play an importent role in the signaling pathways that link the mechanical forces created by distraction to biological responses and in promting new bone formation. Using a rabbit's mandible, we investigated the expression of BMP-2, -4 at different time points during distraction osteogenesis. The purpose of this study is to research the pattern of expression of BMP-2, -4 in new bone formation during distraction osteogenesis of the rabbit mandible. The experimental group was applied gradual distraction (0.7mm a day by twice a day, 4.9mm in total, for 7 days) and the control group was carried out osteotomy alone. They were examined clinically, histologically, and by RT-PCR analysis. On 3 days after osteotomy, the high level of expression of BMP-2, -4 was detected. But, the expression of BMP-4 was decreased during latency period. As distraction was started, its expression was increased and maintained till postoperative 28days. In control group, the expression of BMP-4was remarkably decreased till postoperative 14 days. On the other hand, the expression of BMP-2 was no difference between experimental group and control group. The expression of BMP-4 was maintanined at high level during the entire experimental period in both group. These findings suggested that excellent bone formation during distraction osteogenesis is associated with enhanced expression of BMP-4 genes by mechanical tension stress.

The role of bone morphogenetic protein in the tooth culture

Objectives : The proper development of the facial structures relies upon a sequence of tightly regulated signaling interactions between the ectoderm and mesoderm involving the participation of several families of signaling molecules. Among these, bone morphogenetic proteins (BMPs) have been suggested to be a key signal that regulates the development of the mandible and the initiation and morphogenesis of the teeth. The aim of this study was to examine the artificial development of the mandibular structures and to examine the role of BMPs on tooth morphogenesis and differentiation using an organ culture system. Materials and Methods : The tooth germs from Ed 11.5, 13.5 mice were dissected, and transplanted into the diastema of the mandible primordia. The mandibles containing the transplanted tooth germs were cultured in vitro. During this period, beads soaked with BMP4 were implanted around the transplanted tooth germs. In addition, a diastema block containing the transplanted tooth germ was dissected, then transferred to an adult mouse kidney. After the organ culture, the developing mandibular explant was removed from the kidney and prepared for the tissue specimens. Odontogeneis of the transplanted tooth germs was examined after Hematoxylin-eosin, Masson-trichrome staining. Results : Proliferation and differentiation of the tooth germs cultured in the diastema was observed. In the BMP4-treated tooth germs, the formation of the first and second molars was noted. The crown of the developing tooth showed the formation of a mature cusp with the deposition of enamel and dentin matrix. In conclusion, it was confirmed that BMP4 is involved in the formation of a dental crown and the differentiation of ameloblasts and odontoblasts of the molar tooth during the development of the transplanted tooth germs.

Expressions of noggin mRNA and BMP4 mRNA in rat frontal cortex and hippocampus during different developmental stages / 第三军医大学学报

Objective To observe the expression changes of noggin mRNA and BMP4 mRNA in the hippocampus and frontal cortex of rats at different stages. Methods The expressions of noggin mRNA and BMP4 mRNA were analyzed by the method of reverse transcriptase polymerase chain reaction (RT PCR).Results It was revealed that the level of noggin mRNA in the frontal cortex decreased significantly in P1W rats but high level of BMP4 mRNA was detected in P1M and P3M rats. The expressions of noggin mRNA and BMP4 mRNA in the hippocampus showed the opposite expression pattern. The peak of noggin mRNA expression in the hippocampus was found in E13 and E16 rats. The expression of noggin mRNA decreased gradually but that of BMP4 mRNA in hippocampus increased gradually during the developmental stage. The peak of the expression of BMP4 mRNA was found in P1M rats. Conclusion There are expressions of noggin mRNA and BMP4 mRNA in the frontal cortex and hippocampus in rats at different developmental stages. The expression level is closely correlated with the developmental age. This indicates that noggin and BMP4 play important roles in the development of rat frontal cortex and hippocampus.

EXPRESSION OF BMP4 IN CNS NEURONS OF THE DEVELOPING RAT / 解剖学报

Objective To examine the expression of BMP4 in CNS of the developing rat. Methods In situ hybridization histochemistry(ISHH) was carried out on tissue sections using specific digoxigenin\|labeled oligonucleotide probe. Results It showed that BMP4 mRNA positive cells were located mainly in cerebellum and olfactory at E16.Strong positive signal was seen in hypoglossal nucleus,and moderate signal also seen in spinocerebellar tract and spinal lemniscus at P1\|2.The number of BMP4 mRNA positive cells was increased in the frontal cortex,parietal cortex,and hippocampus subiculum at P1W.The peak of BMP4 expression was in cortex and periamydaloid cortex.Widely distributed BMP4 mRNA positive cells were detected in cortex and hippocampus of rats at P1M,strong positive signal was observed in temporal CNS at P3M,strong positive signal was observed in hippocampus,temporal corex and periamydaloid cortex,lateral nucleus of thalamus and paraventricular nucleus of hypothalamus.BMP4 mRNA positive cells were also found in corex,hippocampus,hypothalamus and thalamus at P18M.Conclusion\ These results indicated that BMP4 could play an important role in CNS development of rats.