骨再生修复中的骨形态发生蛋白信号通路:精准调节与治疗靶点
|
摘要
背景:骨的修复再生是治疗骨类疾病的难点,骨形态发生蛋白具有强大的调控骨量的功能,是调控骨稳态及骨再生的重要蛋白分子。目的:对骨形态发生蛋白信号通路在骨再生修复中的研究进展进行综述。方法:以"骨形态发生蛋白,Smad分子,组织工程,骨缺损,骨修复,骨类疾病,研究进展,bone morphogenetic protein,Smads,Tissue engineering,Bone defect,bone repair,bone disease,Progress in research"为关键词,检索CNKI、PubMed、Elsevier ScienceDirect、Web of Science等数据库1990至2018年发表的与骨形态发生蛋白信号通路及骨再生修复中相关的文献,将所有文章进行初筛后,对保留的文献进一步的归纳和总结分析。结果与讨论:骨形态发生蛋白分子在长骨、软骨、关节以及肌腱的生长发育中均发挥着重要的作用,骨形态发生蛋白2、7已投入临床上应用,用来治疗骨折不愈合、延迟愈合骨不连以及脊柱融合手术等,但骨形态发生蛋白对于骨再生修复中的强大的调控功能仍然值得进行更深一步的研究。骨形态发生蛋白及其相关分子在促进骨再生中取得了巨大进展,实现对骨形态发生蛋白信号的精准调节可能成为治疗骨类疾病的潜在治疗靶点。
BACKGROUND: Bone repair and regeneration is a difficulty in the treatment of bone diseases. Bone morphogenetic proteins can regulate bone mass and are critical for regulating bone homeostasis and bone regeneration.OBJECTIVE: To review the research progress of bone morphogenetic protein signal pathway in bone regeneration and repair.METHODS: Databases of CNKI, Pub Med, Elsevier Science Direct, and Web of Science were retrieved with the keywords of "bone morphogenetic protein, Smads, tissue engineering, bone defect, bone repair, bone disease, progress in research" in English and Chinese,respectively from 1990 to 2018. Related literature on bone morphogenetic protein signaling pathways in bone regeneration was searched.After initial screening, eligible articles were further summarized and analyzed.RESULTS AND CONCLUSION: Bone morphogenetic protein molecules play an important role in the growth and development of long bone,cartilage, tendon and joints. Bone morphogenetic proteins 2 and 7 have been applied in the treatment of fracture nonunion, delayed union,and spine fusion, but bone morphogenetic protein regulation in the bone regeneration and repair still needs a further investigation. Roles of bone morphogenetic proteins and its related molecules in bone regeneration have made great progress. Precise regulation of bone morphogenetic protein signals may become a potential therapeutic target for bone diseases.
BACKGROUND: Bone repair and regeneration is a difficulty in the treatment of bone diseases. Bone morphogenetic proteins can regulate bone mass and are critical for regulating bone homeostasis and bone regeneration.OBJECTIVE: To review the research progress of bone morphogenetic protein signal pathway in bone regeneration and repair.METHODS: Databases of CNKI, Pub Med, Elsevier Science Direct, and Web of Science were retrieved with the keywords of "bone morphogenetic protein, Smads, tissue engineering, bone defect, bone repair, bone disease, progress in research" in English and Chinese,respectively from 1990 to 2018. Related literature on bone morphogenetic protein signaling pathways in bone regeneration was searched.After initial screening, eligible articles were further summarized and analyzed.RESULTS AND CONCLUSION: Bone morphogenetic protein molecules play an important role in the growth and development of long bone,cartilage, tendon and joints. Bone morphogenetic proteins 2 and 7 have been applied in the treatment of fracture nonunion, delayed union,and spine fusion, but bone morphogenetic protein regulation in the bone regeneration and repair still needs a further investigation. Roles of bone morphogenetic proteins and its related molecules in bone regeneration have made great progress. Precise regulation of bone morphogenetic protein signals may become a potential therapeutic target for bone diseases.
引文
[1]Luu HH,Song WX,Luo X,et al.Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells.JOrthop Res.2007;25(5):665-677.
[2]Abula K,Muneta T,Miyatake K,et al.Elimination of BMP7 from the developing limb mesenchyme leads to articular cartilage degeneration and synovial inflammation with increased age.FEBS letters.2015;589:1240-1248.
[3]Razzouk S,Sarkis R.BMP-2:biological challenges to its clinical use.The New York state dental journal.2012;78:37-39.
[4]Smoljanovic T,Caric D,Bojanic I.RE:Clinical applications of bone morphogenetic proteins:current evidence.Kanakaris,NK;Giannoudis,PV;JSOA 17(3):133-46,2008.J Surg Orthop Adv.2010 Summer;19(2):135-137;author reply 137.
[5]Noel D,Gazit D,Bouquet C,et al.Short-term BMP-2 expression is sufficient for in vivo osteochondral differentiation of mesenchymal stem cells.Stem cells 2004;22:74-85.
[6]Tsuji K,Bandyopadhyay A,Harfe BD,et al.BMP2 activity,although dispensable for bone formation,is required for the initiation of fracture healing.Nature genetics.2006;38:1424-1429.
[7]Tan TY,Gonzaga-Jauregui C,Bhoj EJ,et al.Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial,skeletal,and cardiac features overlapping those of 20p12 deletions.Am J Hum Genet.2017 Dec 7;101(6):985-994.
[8]Luo G,Hofmann C,Bronckers AL,et al.BMP-7 is an inducer of nephrogenesis,and is also required for eye development and skeletal patterning.Genes Dev.1995 Nov 15;9(22):2808-2820.
[9]Solloway MJ,Dudley AT,Bikoff EK,et al.Mice lacking Bmp6 function.Dev genet.1998;22:321-339.
[10]Daluiski A,Engstrand T,Bahamonde ME,et al.Bone morphogenetic protein-3 is a negative regulator of bone density.Nature genet.2001;27:84-88.
[11]Celil AB,Hollinger JO,Campbell PG.Osx transcriptional regulation is mediated by additional pathways to BMP2/Smad signaling.J Cell Biochem.2005 Jun 1;95(3):518-528.
[12]Kang Q,Song WX,Luo Q,et al.A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells.Stem cells Dev.2009;18:545-559.
[13]Luu HH,Song WX,Luo X,et al.Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells.JOrthop Res.2007;25:665-677.
[14]Hak DJ,Fitzpatrick D,Bishop JA,et al.Delayed union and nonunions:epidemiology,clinical issues,and financial aspects.Injury.2014;45Suppl 2:S3-7.
[15]Xavier JR,Thakur T,Desai P,et al.Bioactive nanoengineered hydrogels for bone tissue engineering:a growth-factor-free approach.ACS nano.2015;9:3109-3118.
[16]Bez M,Sheyn D,Tawackoli W,et al.In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs.Sci Transl Med.2017 May 17;9(390).pii:eaal3128.
[17]Li C,Jiang C,Deng Y,et al.RhBMP-2 loaded 3D-printed mesoporous silica/calcium phosphate cement porous scaffolds with enhanced vascularization and osteogenesis properties.Sci Rep.2017;7:41331.
[18]Lee SJ,Lee D,Yoon TR,et al.Surface modification of 3D-printed porous scaffolds via mussel-inspired polydopamine and effective immobilization of rhBMP-2 to promote osteogenic differentiation for bone tissue engineering.Acta biomaterialia.2016;40:182-91.
[19]Huang KH,Lin YH,Shie MY,et al.Effects of bone morphogenic protein-2 loaded on the 3D-printed MesoCS scaffolds.J Formos Med Assoc.2018;117(10):879-887.
[20]Chen TH,Ghayor C,Siegenthaler B,et al.Lattice microarchitecture for bone tissue engineering from calcium-phosphate compared to titanium Tissue Eng Part A.2018;24(19-20):1554-1561.
[21]Grimsrud CD,Romano PR,D'Souza M,et al.BMP signaling stimulates chondrocyte maturation and the expression of Indian hedgehog.J Orthop Res.2001;19(1):18-25.
[22]De Luca F,Barnes KM,Uyeda JA,et al.Regulation of growth plate chondrogenesis by bone morphogenetic protein-2.Endocrinology.2001;142:430-436.
[23]Minina E,Kreschel C,Naski MC,et al.Interaction of FGF,Ihh/Pthlh,and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation.Dev cell.2002;3:439-449.
[24]Kobayashi T,Lyons KM,McMahon AP,et al.BMP signaling stimulates cellular differentiation at multiple steps during cartilage development.Proc Natl Acad Sci U S A.2005 Dec 13;102(50):18023-18027.
[25]Komatsu Y,Kaartinen V,Mishina Y.Cell cycle arrest in node cells governs ciliogenesis at the node to break left-right symmetry.Development.2011;138:3915-3920.
[26]Hayashi M,Muneta T,Ju YJ,et al.Weekly intra-articular injections of bone morphogenetic protein-7 inhibits osteoarthritis progression.Arthritis Res Ther.2008;10(5):R118.
[27]Sekiya I,Tang T,Hayashi M,et al.Periodic knee injections of BMP-7delay cartilage degeneration induced by excessive running in rats.JOrthop Res.2009;27(8):1088-1092.
[28]Takahashi T,Muneta T,Tsuji K,et al.BMP-7 inhibits cartilage degeneration through suppression of inflammation in rat zymosan-induced arthritis.Cell Tissue Res.2011;344:321-332.
[29]Ozeki N,Muneta T,Koga H,et al.Transplantation of Achilles tendon treated with bone morphogenetic protein 7 promotes meniscus regeneration in a rat model of massive meniscal defect.Arthritis Rheum.2013;65(11):2876-2886.
[30]Blaney Davidson EN,Vitters EL,et al.Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage.Ann Rheum Dis.2015;74(6):1257-1264.
[31]Simson JA,Strehin IA,Lu Q,et al.An adhesive bone marrow scaffold and bone morphogenetic-2 protein carrier for cartilage tissue engineering.Biomacromolecules.2013;14:637-643.
[32]Duprez D,Bell EJ,Richardson MK,et al.Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb.Mech Dev.1996;57(2):145-157.
[33]Kutz WE,Wang LW,Dagoneau N,et al.Functional analysis of an ADAMTS10 signal peptide mutation in Weill-Marchesani syndrome demonstrates a long-range effect on secretion of the full-length enzyme.Human Mutat.2008;29:1425-1434.
[34]Lee KS,Hong SH,Bae SC.Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein.Oncogene.2002;21:7156-7163.
[35]Afzal F,Pratap J,Ito K,et al.Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription.J Cell Physiol.2005;204(1):63-72.
[36]Franceschi RT,Xiao G.Regulation of the osteoblast-specific transcription factor,Runx2:responsiveness to multiple signal transduction pathways.J Cell Biochem.2003;88(3):446-454.
[37]Wang M,Jin H,Tang D,et al.Smad1 plays an essential role in bone development and postnatal bone formation.Osteoarthritis Cartilage.2011;19(6):751-762.
[38]Keller B,Yang T,Chen Y,et al.Interaction of TGFbeta and BMPsignaling pathways during chondrogenesis.PloS one.2011;6:e16421.
[39]Retting KN,Song B,Yoon BS,et al.BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation.Development.2009;136:1093-1104.
[40]Shore EM,Xu M,Feldman GJ,et al.A recurrent mutation in the BMPtype I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.Nature genetics.2006;38:525-527.
[41]Shen Q,Little SC,Xu M,et al.The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization.J Clin Invest.2009;119(11):3462-3472.
[42]Medici D,Shore EM,Lounev VY,et al.Conversion of vascular endothelial cells into multipotent stem-like cells.Nature Med.2010;16:1400-1406.
[43]Hatsell SJ,Idone V,Wolken DM,et al.ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.Sci Transl Med.2015;7(303):303ra137.
[44]van Dinther M,Visser N,de Gorter DJ,et al.ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation.J Bone Miner Res.2010;25(6):1208-1215.
[45]Hao J,Ho JN,Lewis JA,et al.In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMPinhibitors.ACS chemical biology 2010;5:245-253.
[46]Yu PB,Deng DY,Lai CS,et al.BMP type I receptor inhibition reduces heterotopic[corrected]ossification.Nature medicine.2008;14:1363-1369.
[47]Yang C,Yang L,Wan M,et al.Generation of a mouse model with expression of bone morphogenetic protein type II receptor lacking the cytoplasmic domain in osteoblasts.Ann N Y Acad Sci.2010;1192:286-291.
[48]Mishina Y,Starbuck MW,Gentile MA,et al.Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling.J Biol Chem.2004;279(26):27560-27566.
[49]Yoon BS,Ovchinnikov DA,Yoshii I,et al.Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo.Proc Natl Acad Sci U S A.2005;102(14):5062-5067.
[50]Zou H,Wieser R,Massague J,et al.Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage.Genes Dev.1997;11(17):2191-2203.
[51]Sahni V,Mukhopadhyay A,Tysseling V,et al.BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury.JNeurosci.2010;30(5):1839-1855.
[52]Miyazono K.Signal transduction by bone morphogenetic protein receptors:functional roles of Smad proteins.Bone.1999;25:91-93.
[53]Itoh F,Asao H,Sugamura K,et al.Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads.EMBO J.2001;20(15):4132-4142.
[54]Bai S,Shi X,Yang X,et al.Smad6 as a transcriptional corepressor.JBiol Chem.2000;275(12):8267-8270.
[55]Luo K,Stroschein SL,Wang W,et al.The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling.Genes Dev.1999;13(17):2196-2206.
[56]Wang W,Mariani FV,Harland RM,et al.Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells.Proc Natl Acad Sci U S A.2000;97(26):14394-14399.
[57]Lana DP,Leferovich JM,Kelly AM,et al.Selective expression of a ski transgene affects IIb fast muscles and skeletal structure.Dev Dyn.1996;205(1):13-23.
[58]Guehenneux F,Duret L,Callanan MB,et al.Cloning of the mouse BTG3 gene and definition of a new gene family(the BTG family)involved in the negative control of the cell cycle.Leukemia.1997;11(3):370-375.
[59]Ajima R,Ikematsu N,Ohsugi M,et al.Cloning and characterization of the mouse tob2 gene.Gene 2000;253:215-220.
[60]Yoshida Y,Tanaka S,Umemori H,et al.Negative regulation of BMP/Smad signaling by Tob in osteoblasts.Cell.2000;103:1085-1097.
[61]Zhu H,Kavsak P,Abdollah S,et al.A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.Nature.1999;400:687-693.
[62]Zhang Y,Chang C,Gehling DJ,et al.Regulation of Smad degradation and activity by Smurf2,an E3 ubiquitin ligase.Proc Natl Acad Sci U SA.2001;98(3):974-979.
[63]Zimmerman LB,De Jesus-Escobar JM,Harland RM.The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4.Cell.1996;86:599-606.
[64]Aspenberg P,Jeppsson C,Economides AN.The bone morphogenetic proteins antagonist Noggin inhibits membranous ossification.J Bone Miner Res.2001;16(3):497-500.
[65]Gazzerro E,Du Z,Devlin RD,et al.Noggin arrests stromal cell differentiation in vitro.Bone.2003;32:111-119.
[66]Bachiller D,Klingensmith J,Kemp C,et al.The organizer factors Chordin and Noggin are required for mouse forebrain development.Nature.2000;403:658-661.
[67]Fainsod A,Deissler K,Yelin R,et al.The dorsalizing and neural inducing gene follistatin is an antagonist of BMP-4.Mech Dev.1997;63(1):39-50.
[68]Zohar R,McCulloch CA,Sampath K,et al.Flow cytometric analysis of recombinant human osteogenic protein-1(BMP-7)responsive subpopulations from fetal rat calvaria based on intracellular osteopontin content.Matrix Biol.1998;16(6):295-306.
[2]Abula K,Muneta T,Miyatake K,et al.Elimination of BMP7 from the developing limb mesenchyme leads to articular cartilage degeneration and synovial inflammation with increased age.FEBS letters.2015;589:1240-1248.
[3]Razzouk S,Sarkis R.BMP-2:biological challenges to its clinical use.The New York state dental journal.2012;78:37-39.
[4]Smoljanovic T,Caric D,Bojanic I.RE:Clinical applications of bone morphogenetic proteins:current evidence.Kanakaris,NK;Giannoudis,PV;JSOA 17(3):133-46,2008.J Surg Orthop Adv.2010 Summer;19(2):135-137;author reply 137.
[5]Noel D,Gazit D,Bouquet C,et al.Short-term BMP-2 expression is sufficient for in vivo osteochondral differentiation of mesenchymal stem cells.Stem cells 2004;22:74-85.
[6]Tsuji K,Bandyopadhyay A,Harfe BD,et al.BMP2 activity,although dispensable for bone formation,is required for the initiation of fracture healing.Nature genetics.2006;38:1424-1429.
[7]Tan TY,Gonzaga-Jauregui C,Bhoj EJ,et al.Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial,skeletal,and cardiac features overlapping those of 20p12 deletions.Am J Hum Genet.2017 Dec 7;101(6):985-994.
[8]Luo G,Hofmann C,Bronckers AL,et al.BMP-7 is an inducer of nephrogenesis,and is also required for eye development and skeletal patterning.Genes Dev.1995 Nov 15;9(22):2808-2820.
[9]Solloway MJ,Dudley AT,Bikoff EK,et al.Mice lacking Bmp6 function.Dev genet.1998;22:321-339.
[10]Daluiski A,Engstrand T,Bahamonde ME,et al.Bone morphogenetic protein-3 is a negative regulator of bone density.Nature genet.2001;27:84-88.
[11]Celil AB,Hollinger JO,Campbell PG.Osx transcriptional regulation is mediated by additional pathways to BMP2/Smad signaling.J Cell Biochem.2005 Jun 1;95(3):518-528.
[12]Kang Q,Song WX,Luo Q,et al.A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells.Stem cells Dev.2009;18:545-559.
[13]Luu HH,Song WX,Luo X,et al.Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells.JOrthop Res.2007;25:665-677.
[14]Hak DJ,Fitzpatrick D,Bishop JA,et al.Delayed union and nonunions:epidemiology,clinical issues,and financial aspects.Injury.2014;45Suppl 2:S3-7.
[15]Xavier JR,Thakur T,Desai P,et al.Bioactive nanoengineered hydrogels for bone tissue engineering:a growth-factor-free approach.ACS nano.2015;9:3109-3118.
[16]Bez M,Sheyn D,Tawackoli W,et al.In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs.Sci Transl Med.2017 May 17;9(390).pii:eaal3128.
[17]Li C,Jiang C,Deng Y,et al.RhBMP-2 loaded 3D-printed mesoporous silica/calcium phosphate cement porous scaffolds with enhanced vascularization and osteogenesis properties.Sci Rep.2017;7:41331.
[18]Lee SJ,Lee D,Yoon TR,et al.Surface modification of 3D-printed porous scaffolds via mussel-inspired polydopamine and effective immobilization of rhBMP-2 to promote osteogenic differentiation for bone tissue engineering.Acta biomaterialia.2016;40:182-91.
[19]Huang KH,Lin YH,Shie MY,et al.Effects of bone morphogenic protein-2 loaded on the 3D-printed MesoCS scaffolds.J Formos Med Assoc.2018;117(10):879-887.
[20]Chen TH,Ghayor C,Siegenthaler B,et al.Lattice microarchitecture for bone tissue engineering from calcium-phosphate compared to titanium Tissue Eng Part A.2018;24(19-20):1554-1561.
[21]Grimsrud CD,Romano PR,D'Souza M,et al.BMP signaling stimulates chondrocyte maturation and the expression of Indian hedgehog.J Orthop Res.2001;19(1):18-25.
[22]De Luca F,Barnes KM,Uyeda JA,et al.Regulation of growth plate chondrogenesis by bone morphogenetic protein-2.Endocrinology.2001;142:430-436.
[23]Minina E,Kreschel C,Naski MC,et al.Interaction of FGF,Ihh/Pthlh,and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation.Dev cell.2002;3:439-449.
[24]Kobayashi T,Lyons KM,McMahon AP,et al.BMP signaling stimulates cellular differentiation at multiple steps during cartilage development.Proc Natl Acad Sci U S A.2005 Dec 13;102(50):18023-18027.
[25]Komatsu Y,Kaartinen V,Mishina Y.Cell cycle arrest in node cells governs ciliogenesis at the node to break left-right symmetry.Development.2011;138:3915-3920.
[26]Hayashi M,Muneta T,Ju YJ,et al.Weekly intra-articular injections of bone morphogenetic protein-7 inhibits osteoarthritis progression.Arthritis Res Ther.2008;10(5):R118.
[27]Sekiya I,Tang T,Hayashi M,et al.Periodic knee injections of BMP-7delay cartilage degeneration induced by excessive running in rats.JOrthop Res.2009;27(8):1088-1092.
[28]Takahashi T,Muneta T,Tsuji K,et al.BMP-7 inhibits cartilage degeneration through suppression of inflammation in rat zymosan-induced arthritis.Cell Tissue Res.2011;344:321-332.
[29]Ozeki N,Muneta T,Koga H,et al.Transplantation of Achilles tendon treated with bone morphogenetic protein 7 promotes meniscus regeneration in a rat model of massive meniscal defect.Arthritis Rheum.2013;65(11):2876-2886.
[30]Blaney Davidson EN,Vitters EL,et al.Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage.Ann Rheum Dis.2015;74(6):1257-1264.
[31]Simson JA,Strehin IA,Lu Q,et al.An adhesive bone marrow scaffold and bone morphogenetic-2 protein carrier for cartilage tissue engineering.Biomacromolecules.2013;14:637-643.
[32]Duprez D,Bell EJ,Richardson MK,et al.Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb.Mech Dev.1996;57(2):145-157.
[33]Kutz WE,Wang LW,Dagoneau N,et al.Functional analysis of an ADAMTS10 signal peptide mutation in Weill-Marchesani syndrome demonstrates a long-range effect on secretion of the full-length enzyme.Human Mutat.2008;29:1425-1434.
[34]Lee KS,Hong SH,Bae SC.Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein.Oncogene.2002;21:7156-7163.
[35]Afzal F,Pratap J,Ito K,et al.Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription.J Cell Physiol.2005;204(1):63-72.
[36]Franceschi RT,Xiao G.Regulation of the osteoblast-specific transcription factor,Runx2:responsiveness to multiple signal transduction pathways.J Cell Biochem.2003;88(3):446-454.
[37]Wang M,Jin H,Tang D,et al.Smad1 plays an essential role in bone development and postnatal bone formation.Osteoarthritis Cartilage.2011;19(6):751-762.
[38]Keller B,Yang T,Chen Y,et al.Interaction of TGFbeta and BMPsignaling pathways during chondrogenesis.PloS one.2011;6:e16421.
[39]Retting KN,Song B,Yoon BS,et al.BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation.Development.2009;136:1093-1104.
[40]Shore EM,Xu M,Feldman GJ,et al.A recurrent mutation in the BMPtype I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.Nature genetics.2006;38:525-527.
[41]Shen Q,Little SC,Xu M,et al.The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization.J Clin Invest.2009;119(11):3462-3472.
[42]Medici D,Shore EM,Lounev VY,et al.Conversion of vascular endothelial cells into multipotent stem-like cells.Nature Med.2010;16:1400-1406.
[43]Hatsell SJ,Idone V,Wolken DM,et al.ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.Sci Transl Med.2015;7(303):303ra137.
[44]van Dinther M,Visser N,de Gorter DJ,et al.ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation.J Bone Miner Res.2010;25(6):1208-1215.
[45]Hao J,Ho JN,Lewis JA,et al.In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMPinhibitors.ACS chemical biology 2010;5:245-253.
[46]Yu PB,Deng DY,Lai CS,et al.BMP type I receptor inhibition reduces heterotopic[corrected]ossification.Nature medicine.2008;14:1363-1369.
[47]Yang C,Yang L,Wan M,et al.Generation of a mouse model with expression of bone morphogenetic protein type II receptor lacking the cytoplasmic domain in osteoblasts.Ann N Y Acad Sci.2010;1192:286-291.
[48]Mishina Y,Starbuck MW,Gentile MA,et al.Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling.J Biol Chem.2004;279(26):27560-27566.
[49]Yoon BS,Ovchinnikov DA,Yoshii I,et al.Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo.Proc Natl Acad Sci U S A.2005;102(14):5062-5067.
[50]Zou H,Wieser R,Massague J,et al.Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage.Genes Dev.1997;11(17):2191-2203.
[51]Sahni V,Mukhopadhyay A,Tysseling V,et al.BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury.JNeurosci.2010;30(5):1839-1855.
[52]Miyazono K.Signal transduction by bone morphogenetic protein receptors:functional roles of Smad proteins.Bone.1999;25:91-93.
[53]Itoh F,Asao H,Sugamura K,et al.Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads.EMBO J.2001;20(15):4132-4142.
[54]Bai S,Shi X,Yang X,et al.Smad6 as a transcriptional corepressor.JBiol Chem.2000;275(12):8267-8270.
[55]Luo K,Stroschein SL,Wang W,et al.The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling.Genes Dev.1999;13(17):2196-2206.
[56]Wang W,Mariani FV,Harland RM,et al.Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells.Proc Natl Acad Sci U S A.2000;97(26):14394-14399.
[57]Lana DP,Leferovich JM,Kelly AM,et al.Selective expression of a ski transgene affects IIb fast muscles and skeletal structure.Dev Dyn.1996;205(1):13-23.
[58]Guehenneux F,Duret L,Callanan MB,et al.Cloning of the mouse BTG3 gene and definition of a new gene family(the BTG family)involved in the negative control of the cell cycle.Leukemia.1997;11(3):370-375.
[59]Ajima R,Ikematsu N,Ohsugi M,et al.Cloning and characterization of the mouse tob2 gene.Gene 2000;253:215-220.
[60]Yoshida Y,Tanaka S,Umemori H,et al.Negative regulation of BMP/Smad signaling by Tob in osteoblasts.Cell.2000;103:1085-1097.
[61]Zhu H,Kavsak P,Abdollah S,et al.A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.Nature.1999;400:687-693.
[62]Zhang Y,Chang C,Gehling DJ,et al.Regulation of Smad degradation and activity by Smurf2,an E3 ubiquitin ligase.Proc Natl Acad Sci U SA.2001;98(3):974-979.
[63]Zimmerman LB,De Jesus-Escobar JM,Harland RM.The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4.Cell.1996;86:599-606.
[64]Aspenberg P,Jeppsson C,Economides AN.The bone morphogenetic proteins antagonist Noggin inhibits membranous ossification.J Bone Miner Res.2001;16(3):497-500.
[65]Gazzerro E,Du Z,Devlin RD,et al.Noggin arrests stromal cell differentiation in vitro.Bone.2003;32:111-119.
[66]Bachiller D,Klingensmith J,Kemp C,et al.The organizer factors Chordin and Noggin are required for mouse forebrain development.Nature.2000;403:658-661.
[67]Fainsod A,Deissler K,Yelin R,et al.The dorsalizing and neural inducing gene follistatin is an antagonist of BMP-4.Mech Dev.1997;63(1):39-50.
[68]Zohar R,McCulloch CA,Sampath K,et al.Flow cytometric analysis of recombinant human osteogenic protein-1(BMP-7)responsive subpopulations from fetal rat calvaria based on intracellular osteopontin content.Matrix Biol.1998;16(6):295-306.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |