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Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway

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World Journal of Gastroenterology 2019年第30期25卷 4222-4234页

作者： Gao-Liang Zou Shi Zuo Shuang Lu Rui-Han Hu Yin-Ying Lu Jing Yang Kai-Sheng Deng Ye-Ting Wu Mao Mu Juan-Juan Zhu Jing-Zhang Zeng Bao-Fang Zhang Xian Wu Xue-Ke Zhao Hai-Yang Li Department of Infectious Diseases Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004Guizhou ProvinceChina Department of Hepatobiliary Surgery Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004Guizhou ProvinceChina Comprehensive Liver Cancer Center 302 HospitalBeijing 100039China

BACKGROUND Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer.Early liver fibrosis is reversible by intervention.As a member of the transforming growth factor-beta(TGF-β)superfamily,bone morphogenetic protein 7(BMP7)has anti-liver fibrosis functions.However,little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-βduring liver fibrosis.In addition,the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored.AIM To investigate changes in the dynamic expression of BMP7 during liver fibrosis,interactions between BMP7 and TGF-β1,and possible mechanisms underlying the anti-liver fibrosis function of BMP7.METHODS Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-β1 in mice were observed.Exogenous BMP7 was used to treat mouse primary hepatic stellate cells(HSCs)to observe its effect on activation,migration,and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7.Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin(α-SMA)and the collagen formation associated protein type I collagen(Col I).Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed.RESULTS In the process of liver fibrosis induced by carbon tetrachloride(CCl4)in mice,BMP7 protein expression first increased,followed by a decrease;there was a similar trend in the human body.This process was accompanied by a sustained increase in TGF-β1 protein expression.In vitro experiment results showed that TGF-β1 inhibited BMP7 expression in a time-and dose-dependent manner.In contrast,high doses of exogenous BMP7 inhibited TGF-β1-induced activation,migration,and proliferation of HSCs;this inhibi

关键词： Liver fibrosis Bone morphogenetic protein Transforming growth factor Hepatic stellate cells

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Use of bone morphogenetic proteins in mesenchymal stemcell stimulation of cartilage and bone repair

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World Journal of Stem Cells 2016年第1期8卷 1-12页

作者： Sonia Scarfì Department of Earth Environment and Life SciencesUniversity of Genova16132 GenovaItaly

The extracellular matrix-associated bone morphogenetic proteins(BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their potentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell(MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted celltype lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.

关键词： Mesenchymal stem cells Cartilage Bonerepair Bone morphogenetic protein

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Heterotopic ossification after the use of recombinant human bone morphogenetic protein-7

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World Journal of Orthopedics 2017年第1期8卷 36-41页

作者： Marianthi Papanagiotou Zoe H Dailiana Theophilos Karachalios Sokratis Varitimidis Michael Hantes Georgios Dimakopoulos Marianna Vlychou Konstantinos N Malizos Department of Orthopaedic Surgery Facultyof MedicineUniversity of Thessalia Medical Statistics Epirus Science and Technology ParkUniversity of Ioannina Campus Department of Radiology and Medical Imaging Faculty of MedicineUniversity of Thessalia

AIM To present the incidence of heterotopic ossification after the use of recombinant human bone morphogenetic protein-7(rhB MP-7) for the treatment of nonunions.METHODS Bone morphogenetic proteins(BMPs) promote bone formation by auto-induction. Recombinant human BMP-7 in combination with bone grafts was used in 84 patients for the treatment of long bone nonunions. All patients were evaluated radiographicaly for the development of heterotopic ossification during the standard assessment for the nonunion healing. In all patients(80.9%) with radiographic signs of heterotopic ossification, a CT scan was performed. Nonunion site palpation and ROM evaluation of the adjacent jointswere also carried out. Factors related to the patient(age, gender), the nonunion(location, size, chronicity, number of previous procedures, infection, surrounding tissues condition) and the surgical procedure(graft and fixation type, amount of rhB MP-7) were correlated with the development of heterotopic ossification and statistical analysis with Pearsons χ~2 test was performed.RESULTS Eighty point nine percent of the nonunions treated with rh BMP-7, healed with no need for further procedures. Heterotopic bone formation occurred in 15 of 84 patients(17.8%) and it was apparent in the routine radiologi-cal evaluation of the nonunion site, in a mean time of 5.5 mo after the rh BMP-7 application(range 3-12). The heterotopic ossification was located at the femur in 8 cases, at the tibia in 6, and at the humerus in οne patient. In 4 patients a palpable mass was present and only in one patient, with a para-articular knee nonunion treated with rhB MP-7, the size of heterotopic ossification affected the knee range of motion. All the patients with heterotopic ossification were male. Statistical analysis proved that patient's gender was the only important factor for the development of heterotopic ossification(P = 0.007). CONCLUSION Heterotopic ossification after the use of rh BMP-7 in nonunions was common but it did not compromise the final clinical outc

关键词： Nonunion Bone morphogenetic protein Recombinant human bone morphogenetic protein-7 Heterotopic ossification Long bone Bone graft Osteoinduction

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Bone morphogenetic Protein 15 as a Candidate Gene for Prolificacy of Jining Grey Goat

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畜牧兽医学报 2009年第S1期40卷 1-7页

作者： FENG Tao ZHAO You-zhang CHU Ming-xing DI Ran ZHANG Ying-jie FANG Li College of Animal Science and Technology Gansu Agricultural University Key Laboratory of Farm Animal Genetic Resources and Utilization of Ministry of Agriculture Institute of Animal ScienceChineseAcademy of Agricultural Sciences College of Animal Science and Technology Agricultural University of Hebei

On the basis of the ovine bone morphogenetic protein 15(BMP15)gene,two pairs of primers(PI and P2)were designed to amplify exons 1 and 2 of the BMP15 gene in five randomly selected does of both Angora and Jining Grey goats.The sequences of BMP15 exon 1(P1 amplification)of Angora and Jining Grey goats were identical.There was a 3-nucleotide(CTT)insertion in positions 268 to 270 of goat BMP 15 exon1 compared with that of sheep(GenBank accession number AF236078),which caused a leucine insertion in the 12th position of amino acid sequence.Sequence length of goat BMP 15 exon 2(P2 amplification)was identical with that of sheep(AF236079),but there were seven nucleotide and four amino acid changes between goat and sheep.The nucleotide in the 963rd position of BMP15 exon 2 was A for Angora goat and sheep,and G for Jining Grey goat.Based on this A963G mutation,primer pair P3 was designed to detect single nucleotide polymorphism of BMP15 exon 2 in breeds of high prolificacy(Jining Grey),moderate prolificacy(Boer)and low prolificacy(Angora and Inner Mongolia Cashmere)by polymerase chain reactionsingle strand conformation polymorphism(PCR-SSCP).Three genotypes(AA,AG and GG)were detected in Jining Grey goats,two genotypes(AG and GG)in Boer,and only the AA genotype in Angora and Inner Mongolia Cashmere goats.Sequencing revealed one mutation(A963G)in genotype GG compared with genotype AA,and this mutation resulted in an amino acid change of serine→glycine(S300G).In Jining Grey goats,frequencies of AA,AG and GG genotypes were 0.008,0.059 and 0.933,respectively.Genotypic distributions of the BMP 15 gene were significantly different(P<0.05 or P<0.001)between Jining Grey and Boer,Angora,and Inner Mongolia Cashmere goats.In Jining Grey goats,the does with the GG genotype had 0.71(P<0.05)or 1.57(P<0.05)additional kids than did those with AG or AA genotypes,and does with the AG genotype had 0.86(P<0.05)more kids than did those with the AA genotype.These results tentatively indicate that the BMP15 gene is either a major gene that affect

关键词： goat prolificacy bone morphogenetic protein 15 gene PCR-SSCP

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Use of recombinant human bone morphogenetic protein-2 in spine surgery

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World Journal of Orthopedics 2017年第7期8卷 531-535页

作者： Marios Lykissas Ioannis Gkiatas Department of Spine Surgery Metropolitan Hospital Orthopaedic Department University Hospital of Ioannina

Bone morphogenetic proteins are osteoinductive factors which have gained popularity in orthopaedicsurgery and especially in spine surgery. The use of recombinant human bone morphogenetic protein-2 has been officially approved by the United States Food and Drug Administration only for single level anterior lumbar interbody fusion, nevertheless it is widely used by many surgeons with off-label indications. Despite advantages in bone formation, its use still remains a controversial issue and several complications have been described by authors who oppose their wide use.

关键词： Recombinant human bone morphogenetic protein-2 Spine Fusion Bone graft Yale University Open Data project

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Effect of Danshao Huaxian capsule on Gremlin and bone morphogenetic protein-7 expression in hepatic fibrosis in rats

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World Journal of Gastroenterology 2014年第40期20卷 14875-14883页

作者： Xue-Ke Zhao Ming-Liang Cheng Rong-Min Wu Yu-Mei Yao Mao Mu Juan-Juan Zhu Bao-Fang Zhang Ming-Yu Zhou Department of Infectious Diseases Affiliated Hospital of Guiyang Medical College Department of B Ultrasound Maternal and Child Health Hospital of Guizhou Province

AIM:To observe the effect of Danshao Huaxian capsule(DHC)on the expression of Gremlin and bone morphogenetic protein-7(BMP-7)in the liver of hepatic fibrosis rats.METHODS:A total of 75 male Wistar rats were randomly divided into a normal control group(A),a CCl4-induced hepatic fibrosis model group(B),a natural recovery group(C),a low-dose DHC-treated group(D),and a high-dose DHC-treated group(E),with 15 rats in each group.Liver fibrosis was induced by subcutaneous injections of carbon tetrachloride(CCl4)and a highlipid/low-protein diet for 8 wk,except for the rats in group A.Then,the rats in the two DHC-treated groups were administered 0.5 and 1.0 g/kg DHC by gastrogavage once per day for 8 successive weeks,respectively.By the end of the experiment,the level of transforming growth factorβ1(TGF-β1)in the liver homogenate was determined by an enzyme-linked immunosorbent assay.The mRNA and protein expression of Gremlin and BMP-7 in the liver tissue was determined by reversetranscription polymerase chain reaction,an immunohistochemical assay,and Western blot analysis.RESULTS:Compared with group A,the level of TGF-β1and the mRNA and protein expression of Gremlin were significantly higher in group B(TGF-β1:736.30±24.40μg/g vs 284.20±18.32μg/g,P<0.01;mRNA of Gremlin:80.40±5.46 vs 49.83±4.20,P<0.01;positive protein expression rate of Gremlin:38.46%±1.70%vs 3.83%±0.88%,P<0.01;relative protein expression of Gremlin:2.81±0.24 vs 0.24±0.06,P<0.01),and the mRNA and protein expression of BMP-7was significantly lower in group B(mRNA:54.00±4.34vs 93.99±7.03,P<0.01;positive protein expression rate:28.97%±3.14%vs 58.29%±6.02,P<0.01;relative protein expression:0.48±0.31 vs 1.05±0.12,P<0.01).Compared with groups B and C,the degree of hepatic fibrosis was significantly improved,and the level of TGF-β1 and the mRNA and protein expression of Gremlin were significantly lowered in the two DHCtreated groups(TGF-β1:523.14±21.29μg/g,441.86±23.18μg/g vs 736.30±24.40μg/g,651.13±15.75μg/g,P<0.01;mRNA of Gremlin:64.86±2.83,55.82±5.39 vs 80.40±5

关键词： Hepatic fibrosis Bone morphogenetic protein Gremli

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Exogenous bone morphogenetic protein-7 reduces hepatic fibrosis inSchistosoma japonicum-infected micevia transforming growth factor-β/Smad signaling

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World Journal of Gastroenterology 2013年第9期19卷 1405-1415页

作者： Bo-Lin Chen Jie Peng Qing-Fu Li Min Yang Yuan Wang Wei Chen Department of Gastroenterology Xiangya Hospital Central South University Department of Respiration Hunan Children's Hospital Department of Gastroenterology Changsha Central Hospital

AIM: To investigate the antifibrotic effects of bone morphogenetic protein-7 (BMP-7) on Schistosoma japonicum (S. japonicum )-induced hepatic fibrosis in BALB/C mice. METHODS: Sixty BALB/C mice were randomly divided into three groups, including a control group (group A, n = 20), model group (group B, n = 20) and BMP-7 treated group (group C, n = 20). The mice in group B and group C were abdominally infected with S. japonicum cercariae to induce a schistosomal hepatic fibrosis model. The mice in group C were administered human recombinant BMP-7. Liver samples were extracted from mice sacrificed at 9 and 15 wk after modeling. Hepatic histopathological changes were assessed using Masson's staining. Transforming growth factor-beta 1 (TGF-β1), alpha-smooth muscle actin (α-SMA), phosphorylated Smad2/3 (pSmad2/3) and Smad7 protein levels and localization were measured by Western blotting and immunohistochemistry, respectively, and their mRNA expressions were detected by reverse transcriptionpolymerase chain reaction (RT-PCR). RESULTS: The schistosomal hepatic fibrosis mouse model was successfully established, as the livers of mice in group B and group C showed varying degrees of typical schistosomal hepatopathologic changes such as egg granuloma and collagen deposition. The degree of collagen deposition in group C was higher than that in group A (week 9: 22.95±6.66vs 2.02±0.76; week 15: 12.84±4.36 vs 1.74±0.80; P<0.05), but significantly lower than that in group B (week 9: 22.95±6.66 vs 34.43±6.96; week 15: 12.84±4.36 vs 18.90±5.07;P<0.05) at both time points. According to immunohistochemistry data, the expressions of α-SMA, TGF-β1 and pSmad2/3 protein in group C were higher than those in group A (α-SMA: week 9: 21.24±5.73 vs 0.33±0.20; week 15: 12.42±4.88 vs 0.34±0.27; TGF-β1: week 9: 37.00±13.74 vs 3.73±2.14; week 15: 16.71±9.80 vs 3.08±2.35; pSmad2/3: week 9: 12.92±4.81 vs 0.83±0.48; week 15: 7.87±4.09 vs 0.90±0.45; P<0.05), but significantly lower than those in group B (α-SMA: week 9: 21.24±5.73 vs 34.39±5.74; week

关键词： Bone morphogenetic protein-7 Schistosoma japonicum Hepatic fibrosis Smad BALB/C mice

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rhBMP in lumber fusion for lumbar spondylolisthesis: A systematic review and meta-analysis

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Chinese Journal of Traumatology 2019年第1期22卷 51-58页

作者： Peng-Fei Han Tao-Yu Chen Zhi-Liang Zhang Xiao-Dong Li Peng-Cui Li Lei Wei Zhi Lu Xiao-Chun Wei Department of Orthopaedic The Second People's Hospital of Changzhi Changzhi Shanxi Province China Department of Orthopaedic The Second Clinical Medical College of Shanxi Medical University Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair Taiyuan Shanxi Province China

Purpose: To compare the efficacy and safety of recombinant human bone morphogenetic protein (rhBMP) and iliac crest autograft in the fusion treatment of lumbar spondylolisthesis. Methods: The studies using randomized con trolled trials to compare the rhBMP with iliac crest autograft in the treatment of lumbar spondylolisthesis were retrieved from Embase, Pubmed, ProQuest dissertations & theses (PQDT), China national knowledge infrastructure (CNKI), Chinese Biomedical Database, Wanfang Data, Cochrane Library (from March 1998 to March 2018). Postoperative fusion rate, clinical success rate, postoperative intervertebral height, complications, operation time, blood loss and duration of hospitalization were chosen as the outcome indicators. Methodological quality of the trials was critically assessed, and releva nt data were extracted. Statistical software Revman 5.3 was used for dataanalysis. Results: Eleven articles were included in the meta-analysis. The results showed that, comparing the efficacy of rhBMP with iliac crest autograft, statistical significance was found in the 24-month fusion rate post operation [95% CI (1.38, 24.70), p = 0.02] and operation time [95% CI (-14.22,-2.08), p = 0.008]. There is not sufficient evidence for statistical differences in the remaining indicators. Conclusion: The current literature shows rhBMP is a safe and effective grafting material in the treatment of lumbar spondylolisthesis. Further evidenee is dependent on the emergence of more randomized controlled trials with higher quality and larger sample sizes in the future.

关键词： Spondylolysis Bone morphogenetic proteins Ilium Autografts Meta-analysis

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BMP-4 induced proliferation and oriented differentiation of rat hepatic oval cells into hepatocytes

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Asian Pacific Journal of Tropical Medicine 2015年第5期8卷 412-416页

作者： Zhi-Ming Wang Xiao-Hua Yuan Hong Shen Department of Hepatobiliary Surgery Xiangya HospitalCentral South University Institute of Medical Science Xiangya HospitalCentral South University

Objective:To explore the role of bone morphogenetic protein 4(BMP-4) in hepatic progenitor cells(HPCs).Methods:The effect of BMP-4 on rat hepatic oval cells was examined by using the WB-F344 rat hepatocytic epithelial stem-cell-like cell line.This hepatocytic cell line could exert various hepatocytc functions including the secretion of albumin and urea.Immunohistochemistry was used to examine the effects of BMP-4 and its antagonist,Noggin,on the proliferation and differentiation of these cells,cellular uptake and excretion of indocyanine green,the periodic acid-schiff(PAS) assay for glycogen storage and the expression of hepatic markers.Results:Our results showed for the first time that BMP-4 may acted as a potential inducer of hepatic differentiation in rat hepatic oval cells.Conclusions:This cell source offers a much-needed attractive and expandable source for future investigations of drug screening,stem cell technologies and cellular transplantation,in a society with increasing levels of liver disease and damage.

关键词： Bone morphogenetic protein-4 Transforming growth factor-β Hepatic progenitor cells Proliferation Differentiation

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The role of Smad signaling in vascular and hematopoietic development revealed by studies using genetic mouse models

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Science China(Life Sciences) 2010年第4期53卷 485-489页

作者： LAN Yu & YANG Xiao State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China State Key Laboratory of Proteomics Genetic Laboratory of Development and Diseases Institute of Biotechnology Beijing China

Smads are intracellular mediators of transforming growth factor β (TGF-β) superfamily signaling. In this review, we focus on the genetic mouse models for Smad pathways, which have provided functional evidence regarding the complex circuitry in angiogenesis and hematopoiesis during development. In the early stages of vascular development, TGF-β signaling is a contri buting factor in angiogenesis and vascular maturation. Whereas in the later embryogenesis, selected molecules of Smad pathways, such as TGF-β type II receptor (TbRII), ALK5, and Smad5, seem to be dispensable for vessel morphogenesis and integrity. TGF-β signaling is not required in the induction of hematopoietic precursors from mesoderm, but inhibits the subsequent expansion of committed hematopoietic precursors. By contrast, bone morphogenetic protein 4 (BMP4) has long been acknowledged pivotal in mesoderm induction and hematopoietic commitment during development. However, recent genetic evidence shows the BMP4-ALK3 axis is not crucial for the formation of hematopoietic cells from FLK1+ mesoderm. Because of the highly redundant mechanisms within the Smad pathways, the precise role of the Smad signaling involved in vascular and hematopoietic development remains nebulous. The generation of novel cell lineage restricted Cre transgenes would shed new light on the future relevant investigations.

关键词： Smad transforming growth factor β (TGF-β) bone morphogenetic protein (BMP) angiogenesis hematopoiesis knockout development

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