遗传性多发性骨软骨瘤的分子生物学特征
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摘要
背景:遗传性多发性骨软骨瘤因较低发病率导致少有能作为临床研究的庞大家系,细胞模型、动物模型复制困难等客观因素存在对研究该疾病的发生发展机制造成了一定困扰。目的:就遗传性多发性骨软骨瘤病理改变、分子机制、信号通路等研究进展做出较为详尽的论述。方法:通过查阅往年国内外相关研究文献,研究基因网站,对相关内容及观点进行整合整理。结果与结论:①遗传性多发性骨软骨瘤是一种常染色体显性遗传性骨骼疾病,特征为多个从长管状骨的干骺端向外生长的覆盖软骨的骨肿瘤,临床症状多变,与肿瘤所在位置、大小及形状等因素有关;②该疾病具有遗传异质性,主要与EXT基因家族的肿瘤抑制基因Exostosin-1(EXT1)或Exostosin-2(EXT2)的突变相关,在分子信号通路上与硫酸乙酰肝素及其下游信号传导通路有关;③综述总结了进几十年对遗传性多发性骨软骨瘤的相关研究,希望为后续研究做出铺垫。
BACKGROUND: Low incidence of hereditary multiple exostoses leads to few lines for clinical research, and difficulty in duplicating cellular and animal models delay the studies on the pathogenesis.OBJECTIVE: To summarize the research progress of pathological changes, molecular mechanisms and signaling pathways of hereditary multiple exostoses.METHODS: By consulting relevant researches at home and abroad and researching the genetic website, we integrated related content and opinions.RESULTS AND CONCLUSION:(1) Hereditary multiple exostoses are an autosomal dominant hereditary skeletal disease characterized by multiple bone neoplasms covered by cartilages that grow outward from the metaphysis of long tubular bones. The clinical symptoms that are related to factors such as location, size and shape are variable.(2) The disease is genetically heterogeneous and is mainly associated with mutations in the tumor suppressor genes Exostosin-1 or Exostosin-2 of the EXT family. The occurrence of the disease is mainly associated with heparin sulfate and its downstream signaling pathways in the molecular level.(3) We have summarized the researches on hereditary multiple exostoses in the past decades and paved the way for future investigation.
BACKGROUND: Low incidence of hereditary multiple exostoses leads to few lines for clinical research, and difficulty in duplicating cellular and animal models delay the studies on the pathogenesis.OBJECTIVE: To summarize the research progress of pathological changes, molecular mechanisms and signaling pathways of hereditary multiple exostoses.METHODS: By consulting relevant researches at home and abroad and researching the genetic website, we integrated related content and opinions.RESULTS AND CONCLUSION:(1) Hereditary multiple exostoses are an autosomal dominant hereditary skeletal disease characterized by multiple bone neoplasms covered by cartilages that grow outward from the metaphysis of long tubular bones. The clinical symptoms that are related to factors such as location, size and shape are variable.(2) The disease is genetically heterogeneous and is mainly associated with mutations in the tumor suppressor genes Exostosin-1 or Exostosin-2 of the EXT family. The occurrence of the disease is mainly associated with heparin sulfate and its downstream signaling pathways in the molecular level.(3) We have summarized the researches on hereditary multiple exostoses in the past decades and paved the way for future investigation.
引文
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[41]Lin X,Wei G,Shi Z,et al.Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice.Dev Biol.2000;224(2):299-311.
[42]Hameetman L,Kok P,Eilers PH,et al.The use of Bcl-2 and PTHLH immunohistochemistry in the diagnosis of peripheral chondrosarcoma in a clinicopathological setting.Virchows Arch.2005;446(4):430-437.
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[45]Koziel L,Kunath M,Kelly OG,et al.Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification.Dev Cell.2004;6(6):801-813.
[46]Benoist-Lasselin C,de Margerie E,Gibbs L,et al.Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients.Bone.2006;39(1):17-26.
[47]Osterholm C,Barczyk MM,Busse M,et al.Mutation in the heparan sulfate biosynthesis enzyme EXT1 influences growth factor signaling and fibroblast interactions with the extracellular matrix.J Biol Chem.2009;284(50):34935-34943.
[48]H?cker U,Nybakken K,Perrimon N.Heparan sulphate proteoglycans:the sweet side of development.Nat Rev Mol Cell Biol.2005;6(7):530-541.
[49]Shimokawa K,Kimura-Yoshida C,Nagai N,et al.Cell surface heparan sulfate chains regulate local reception of FGFsignaling in the mouse embryo.Dev Cell.2011;21(2):257-272.
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[51]Huegel J,Mundy C,Sgariglia F,et al.Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones:a mechanism likely deranged in Hereditary Multiple Exostoses.Dev Biol.2013;377(1):100-12.
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[2]Jones KB.Glycobiology and the growth plate:current concepts in multiple hereditary exostoses.J Pediatr Orthop.2011;31(5):577-586.
[3]Tahasildar N,Sudesh P,Goni V,et al.Giant osteochondroma of axis in a child with multiple hereditary exostoses:case report and review of literature.J Pediatr Orthop B.2012;21(3):280-285.
[4]Franch J,Font J,Ramis A,et al.Multiple cartilaginous exostosis in a Golden Retriever cross-bred puppy.Clinical,radiographic and backscattered scanning microscopy findings.Vet Comp Orthop Traumatol.2005;18(3):189-193.
[5]Kyriazoglou AI,Dimitriadis E,Arnogiannaki N,et al.Similar cytogenetic findings in two synchronous secondary peripheral chondrosarcomas in a patient with multiple osteochondromas.Cancer Genet.2011;204(12):677-681.
[6]郭永成,王永堂,陆亚东,等.儿童遗传性多发性骨软骨瘤软骨帽的超微结构观察[J].临床与实验病理学杂志,2013,29(2):171-174.
[7]Huvos AG,Marcove RC.Chondrosarcoma in the young.Aclinicopathologic analysis of 79 patients younger than 21years of age.Am J Surg Pathol.1987;11(12):930-942.
[8]Legeai-Mallet L,Munnich A,Maroteaux P,et al.Incomplete penetrance and expressivity skewing in hereditary multiple exostoses.Clin Genet.1997;52(1):12-16.
[9]肖福英,蒋林彬,刘健翔,等.遗传性多发性骨软骨瘤一家系11例[J].中华医学遗传学杂志,2005,22(5):574.
[10]Rozeman LB,de Bruijn IH,Bacchini P,et al.Dedifferentiated peripheral chondrosarcomas:regulation of EXT-downstream molecules and differentiation-related genes.Mod Pathol.2009;22(11):1489-1498.
[11]Cook A,Raskind W,Blanton SH,et al.Genetic heterogeneity in families with hereditary multiple exostoses.Am J Hum Genet.1993;53(1):71-79.
[12]Wu YQ,Heutink P,de Vries BB,et al.Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11.Hum Mol Genet.1994;3(1):167-171.
[13]Wuyts W,Ramlakhan S,Van Hul W,et al.Refinement of the multiple exostoses locus(EXT2)to a 3-cM interval on chromosome 11.Am J Hum Genet.1995;57(2):382-387.
[14]Le Merrer M,Legeai-Mallet L,Jeannin PM,et al.A gene for hereditary multiple exostoses maps to chromosome 19p.Hum Mol Genet.1994;3(5):717-722.
[15]Jennes I,Pedrini E,Zuntini M,et al.Multiple osteochondromas:mutation update and description of the multiple osteochondromas mutation database(MOdb).Hum Mutat.2009;30(12):1620-1627.
[16]Ishimaru D,Gotoh M,Takayama S,et al.Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas.BMCGenet.2016;17:52.
[17]Ahn J,Lüdecke HJ,Lindow S,et al.Cloning of the putative tumour suppressor gene for hereditary multiple exostoses(EXT1).Nat Genet.1995;11(2):137-143.
[18]Wuyts W,Van Hul W,Wauters J,et al.Positional cloning of a gene involved in hereditary multiple exostoses.Hum Mol Genet.1996;5(10):1547-1557.
[19]Szuhai K,Jennes I,de Jong D,et al.Tiling resolution array-CGHshows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients.Hum Mutat.2011;32(2):E2036-2049.
[20]Li Y,Wang J,Tang J,et al.Heterogeneous spectrum of EXTgene mutations in Chinese patients with hereditary multiple osteochondromas.Medicine(Baltimore).2018;97:e12855.
[21]Scl S,Impo R,Takata RI,et al.Analysis of mutations in EXT1and EXT2 in Brazilian patients with multiple osteochondromas.Mol Genet Genomic Med.2018;6:382-392.
[22]Wise CA,Clines GA,Massa H,et al.Identification and localization of the gene for EXTL,a third member of the multiple exostoses gene family.Genome Res.1997;7(1):10-16.
[23]Wuyts W,Van Hul W,Hendrickx J,et al.Identification and characterization of a novel member of the EXT gene family,EXTL2.Eur J Hum Genet.1997;5(6):382-389.
[24]Van Hul W,Wuyts W,Hendrickx J,et al.Identification of a third EXT-like gene(EXTL3)belonging to the EXT gene family.Genomics.1998;47(2):230-237.
[25]Kang QL,Xu J,Zhang Z,et al.Mutation screening for the EXT1 and EXT2 genes in Chinese patients with multiple osteochondromas.Arch Med Res.2013;44(7):542-548.
[26]Stancheva-Ivanova MK,Wuyts W,van Hul E,et al.Clinical and molecular studies of EXT1/EXT2 in Bulgaria.J Inherit Metab Dis.2011;34(4):917-921.
[27]Lindahl U.Heparan sulfate-protein interactions--a concept for drug design.Thromb Haemost.2007;98(1):109-115.
[28]Li JP.Heparin,heparan sulfate and heparanase in cancer:remedy for metastasis.Anticancer Agents Med Chem.2008.8(1):64-76.
[29]McCormick C,Leduc Y,Martindale D,et al.The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.Nat Genet.1998;19(2):158-161.
[30]de Andrea CE,Prins FA,Wiweger MI,et al.Growth plate regulation and osteochondroma formation:insights from tracing proteoglycans in zebrafish models and human cartilage.J Pathol.2011;224(2):160-168.
[31]Hameetman L,David G,Yavas A,et al.Decreased EXTexpression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas.J Pathol.2007;211(4):399-409.
[32]Clément A,Wiweger M,der Hardt SV,et al.Regulation of zebrafish skeletogenesis by ext2/dackel and papst1/pinscher.PLoS Genet.2008;4(7):e1000136.
[33]Huegel J,Enomoto-Iwamoto M,Sgariglia F,et al.Heparanase stimulates chondrogenesis and is up-regulated in human ectopic cartilage:a mechanism possibly involved in hereditary multiple exostoses.Am J Pathol.2015;185:1676-1685.
[34]Schwartz NB,Domowicz M.Chondrodysplasias due to proteoglycan defects.Glycobiology.2002;12(4):57R-68R.
[35]Turnbull J,Powell A,Guimond S.Heparan sulfate:decoding a dynamic multifunctional cell regulator.Trends Cell Biol.2001;11(2):75-82.
[36]Hecht JT,Hall CR,Snuggs M,et al.Heparan sulfate abnormalities in exostosis growth plates.Bone.2002;31(1):199-204.
[37]Zak BM,Schuksz M,Koyama E,et al.Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones.Bone.2011;48(5):979-987.
[38]Jones KB,Pacifici M,Hilton MJ.Multiple hereditary exostoses(MHE):elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research.Connect Tissue Res.2014;55(2):80-88.
[39]Duncan G,McCormick C,Tufaro F.The link between heparan sulfate and hereditary bone disease:finding a function for the EXT family of putative tumor suppressor proteins.J Clin Invest.2001;108(4):511-516.
[40]Beltrami G,Ristori G,Scoccianti G,et al.Hereditary Multiple Exostoses:a review of clinical appearance and metabolic pattern.Clin Cases Miner Bone Metab.2016;13(2):110-118.
[41]Lin X,Wei G,Shi Z,et al.Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice.Dev Biol.2000;224(2):299-311.
[42]Hameetman L,Kok P,Eilers PH,et al.The use of Bcl-2 and PTHLH immunohistochemistry in the diagnosis of peripheral chondrosarcoma in a clinicopathological setting.Virchows Arch.2005;446(4):430-437.
[43]Modrowski D,Orosco A,Thévenard J,FromiguéO,Marie PJ.Syndecan-2 overexpression induces osteosarcoma cell apoptosis:Implication of syndecan-2 cytoplasmic domain and JNK signaling.Bone.2005;37(2):180-189.
[44]Mundy C,Bello A,Sgariglia F,et al.HhAntag,a Hedgehog Signaling Antagonist,Suppresses Chondrogenesis and Modulates Canonical and Non-Canonical BMP Signaling.JCell Physiol.2016;231:1033-1044.
[45]Koziel L,Kunath M,Kelly OG,et al.Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification.Dev Cell.2004;6(6):801-813.
[46]Benoist-Lasselin C,de Margerie E,Gibbs L,et al.Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients.Bone.2006;39(1):17-26.
[47]Osterholm C,Barczyk MM,Busse M,et al.Mutation in the heparan sulfate biosynthesis enzyme EXT1 influences growth factor signaling and fibroblast interactions with the extracellular matrix.J Biol Chem.2009;284(50):34935-34943.
[48]H?cker U,Nybakken K,Perrimon N.Heparan sulphate proteoglycans:the sweet side of development.Nat Rev Mol Cell Biol.2005;6(7):530-541.
[49]Shimokawa K,Kimura-Yoshida C,Nagai N,et al.Cell surface heparan sulfate chains regulate local reception of FGFsignaling in the mouse embryo.Dev Cell.2011;21(2):257-272.
[50]Stickens D,Zak BM,Rougier N,et al.Mice deficient in Ext2lack heparan sulfate and develop exostoses.Development.2005;132(22):5055-5068.
[51]Huegel J,Mundy C,Sgariglia F,et al.Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones:a mechanism likely deranged in Hereditary Multiple Exostoses.Dev Biol.2013;377(1):100-12.
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