尼尔样1型生长因子促进修复骨再生和治疗骨质疏松的应用潜力
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摘要
背景:骨缺损再生修复是临床常见难题,骨组织的再生修复需要特定的微环境和生长因子参与。尼尔样1型生长因子(Nel-like molecular 1,Nell-1)是一种分泌性蛋白,同时也是是一种有效且无明显毒副作用的骨生长因子,目前大量研究表明Nell-1能够用于促进骨再生修复,有望成为骨再生修复的新方法。目的:对Nell-1调控成骨机制及其在骨再生修复方面的应用和前景进行综述。方法:以"nell-1,nel-like molecule 1,nel-like protein 1,neural EGF like protein 1,bone repairing,osteogenesis,osteogenic,regenerative medicine"或"Nell-1,nell-1蛋白,nel样1型分子,神经源性表皮生长因子样分子1,骨生成,成骨作用,骨修复,再生医学"等作为检索词,利用PubMed、中国知网、万方数据库、embase进行检索,选择从1996年12月15日至2017年11月1日有关Nell-1生长因子与成骨及骨再生修复应用方面的文献资料,排除重复性研究。结果与结论:Nell-1的发现最早与颅缝早闭相关,后来被证实为一种有效的骨生长因子,其具有抗脂肪分化、抑制炎症反应和无明显毒副作用等优点。目前大量动物实验已证明Nell-1可应用于促进骨再生修复,除此之外,Nell-1同时还有作为治疗骨质疏松症有效药物的巨大潜力,有望在未来成为用于骨再生修复的新方法。
BACKGROUND: Bone regeneration and repair for bone defects is a common problem in the clinic. Bone regeneration requires specific microenvironment and growth factors. Nel-like molecular 1(Nell-1) is a secreted protein, and it is also an effective bone growth factor without toxic effect. Nell-1 has been shown to promote bone regeneration and repair, and it is expected to be a new method for bone regeneration and repair.OBJECTIVE: To review the mechanism of Nell-1 in osteogenesis and its application and prospects in bone regeneration and repair. METHODS: PubMed, CNKI, WanFang and Embase databases were searched for the literature addressing Nell-1 in osteogenesis, bone regeneration and repair published between December 15, 1996 and November 1, 2017. The keywords were "nell-1, nel-like molecule 1, nel-like protein 1, neural EGF like protein 1, bone repairing, osteogenesis, osteogenic, regenerative medicine" in English and Chinese, respectively. The repetitive studies were excluded. RESULTS AND CONCLUSION: Nell-1 was firstly found to be associated with craniosynostosis and later has been proved to be an effective bone growth factor. Nell-1 possesses the roles of anti-adipose differentiation, inhibiting inflammatory reaction without obvious toxic effects. A large number of animal experiments have proven that Nell-1 can be used to promote bone regeneration and repair. Additionally, it is also expected to be a potential drug for osteoporosis, and is a promising method in bone regeneration and repair.
BACKGROUND: Bone regeneration and repair for bone defects is a common problem in the clinic. Bone regeneration requires specific microenvironment and growth factors. Nel-like molecular 1(Nell-1) is a secreted protein, and it is also an effective bone growth factor without toxic effect. Nell-1 has been shown to promote bone regeneration and repair, and it is expected to be a new method for bone regeneration and repair.OBJECTIVE: To review the mechanism of Nell-1 in osteogenesis and its application and prospects in bone regeneration and repair. METHODS: PubMed, CNKI, WanFang and Embase databases were searched for the literature addressing Nell-1 in osteogenesis, bone regeneration and repair published between December 15, 1996 and November 1, 2017. The keywords were "nell-1, nel-like molecule 1, nel-like protein 1, neural EGF like protein 1, bone repairing, osteogenesis, osteogenic, regenerative medicine" in English and Chinese, respectively. The repetitive studies were excluded. RESULTS AND CONCLUSION: Nell-1 was firstly found to be associated with craniosynostosis and later has been proved to be an effective bone growth factor. Nell-1 possesses the roles of anti-adipose differentiation, inhibiting inflammatory reaction without obvious toxic effects. A large number of animal experiments have proven that Nell-1 can be used to promote bone regeneration and repair. Additionally, it is also expected to be a potential drug for osteoporosis, and is a promising method in bone regeneration and repair.
引文
[1]Egol KA,Nauth A,Lee M,et al.Bone Grafting:Sourcing, Timing,Strategies, and Alternatives.J Orthop Trauma. 2015;29 Suppl12:S10-104.
[2]Wang W,Yeung K W K. Bone grafts and biomaterials substitutes for bone defect repair:Areview. Bioactive Materials.2017;2(4):224-247.
[3]Arealis G,Nikolaou VS.Bone printing:new frontiers in the treatment of bone defects. Injury.2015;46 Suppl 8:S20-22.
[4]Yu X,Tang X,Gohil SV, et al.Biomaterials for Bone Regenerative Engineering.Advanced Healthcare Materials.2015;4(9):1268.
[5]张明磊,宋显吉,尹若峰,等.神经源性表皮生长因子样分子-1局部植入促进大鼠长骨干骨折愈合的研究[J].中华实验外科杂志, 2015,32(9):2211-2213.
[6]周海华,李祖兵. Nel样1型分子对成骨细胞分化的分子调控机制[J].国际口腔医学杂志,2010, 37(2):166-169.
[7]Watanabe TK.Cloning and characterization of two novel human cDNAs(NELL1 and NELL2)encoding proteins with six EGF-like repeats.Genomics.1996;38(3):273-276.
[8]万林子,金晗,吴熙凤,等.脂质体介导NELL1基因对脂肪干细胞影响的体外研究[J].现代口腔医学杂志, 2015(3):161-165.
[9]Smith B, Goldstein T, Ekstein C.Biologic adjuvants and bone:current use in orthopedic surgery. Curr Rev Musculoskelet Med.2015;8(2):193-199.
[10]Ting K,Vastardis H,Mulliken JB,et al.Human NELL-1 expressed in unilateral coronal synostosis. J Bone Miner Res.1999;14(1):80-89.
[11]Zhang X,Kuroda S,Carpenter D,et al.Craniosynostosis in transgenic mice overexpressing Nell-1. J Clin Invest. 2002;110(6):861-870.
[12]Zhang X,Carpenter D,Bokui N,et al.Overexpression of Nell-1, a craniosynostosis. J Bone Miner Res. 2003;18(12):2126-2134.
[13]Zhang X, Kang T, Bessette C M, et al. Nell-1, a key Functional Mediator of Runx2, Partially Rescues Calvarial Defects inRunx2+/-Mice.J Bone Miner Res.2011;26(4):777-791.
[14]Zhang X,Péault B,Chen W,et al.The Nell-1 growth factor stimulates bone formation by purified human perivascular cells.Tissue Engineering Part A.2011;17(19-20):2497.
[15]Desai J,Shannon ME,Johnson MD,et al.Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. Human Molecular Genetics.2006;15(8):1329.
[16]Aghaloo T,Cowan CM,Chou YF,et al.Nell-1-induced bone regeneration in calvarial defects.Am J Pathol. 2006;169(3):903-915.
[17]胡镜宙,蒋欣泉,张志愿,等.实时定量PCR检测Nel样I型分子基因对大鼠骨髓基质细胞成骨相关基因表达的影响[J].中国口腔颌面外科杂志,2008, 6(1):48-53.
[18]Fahmygarcia S,Van DM,Wittebuoma J,et al.Nell-1, HMGB1 and CCN2 enhance migration and vasculogenesis, but not osteogenic differentiation compared to BMP2. Tissue Eng Part A. 2018;24(3-4):207-218
[19]Li G,Liu J,Wang Y,et al.LNGFR targets the Wnt/β-catenin pathway and promotes the osteogenic differentiation in rat ectomesenchymal stem cells.Sci Rep.2017;7(1):11021.
[20]Shen J,James AW,Chung J,et al.NELL-1 promotes cell adhesion and differentiation via Integrinβ1. J Cell Biochem. 2012;113(12):3620-3608.
[21]Shen J,James AW,Zhang X,et al.Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2. Am J Pathol. 2016;186(2):419-434.
[22]张弘,姚宇,孙佳栋,等. NELL-1调控RUNX2的P1启动子诱导成骨分化[J].中华口腔医学研究杂志(电子版), 2017, 11(4):197-203.
[23]Li CS,Zhang X,Péault B,et al.Accelerated Chondrogenic Differentiation of Human Perivascular Stem Cells with NELL-1.Tissue Eng Part A.2016;22(3-4):272-285
[24]Mishra R,Sefcik R,Bishop T,et al.Proliferation and Osteogenic Differentiation of Human Mesenchymal Stem Cells on Poly(propylene fumarate)Tissue Engineering Scaffolds[C]//Osuwmc Trainee Research Day. 2015.
[25]Cowan CM,Zhang X,James AW,et al.NELL-1 increases pre-osteoblast mineralization using both phosphate transporter Pit1 and Pit2. Biochem Biophys Res Commun.2012;422(3):351-357.
[26]Liu M,Wang Q,Tang R,et al.Nel-like Molecule 1 Contributes to the Odontoblastic Differentiation of Human Dental Pulp Cells. J Endod.2016;42(1):95-100.
[27]Lee M,Siu RK,Ting K,et al.Effect of Nell-1 delivery on chondrocyte proliferation and cartilaginous extracellular matrix deposition.Tissue Eng Part A.2010;16(5):1791-1800.
[28]James AW,Pan A,Chiang M,et al.A new function of Nell-1 protein in repressing adipogenic differentiation. Biochem Biophys Res Commun.2011;411(1):126-131.
[29]秦雪嫣,赵华翔,张倩,等. NELL-1:高效特异的新型生长因子[J].北京大学学报(医学版),2016,48(2):380-383.
[30]Shen J,James AW,Zara JN,et al.BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1.Tissue Engineering Part A.2013;19(21-22):2390.
[31]郭旭,彭江,王玉,等.腺病毒介导的NELL1基因对小鼠成骨细胞增殖分化的影响[J].解放军医学院学报,2012,33(5):509-511.
[32]陈微微. NELL-1蛋白对小鼠ATDC5细胞软骨分化的调控机制和对人血管周细胞成骨分化作用的研究[D].杭州:浙江大学, 2011.
[33]Lee S, Wang C, Pan HC,et al.Combining Smoothened Agonist(SAG)and NEL-like protein-1(NELL-1)Enhances Bone Healing.Plast Reconstr Surg.2017;139(6):1385-1396
[34]Zhu S,Zhang B,Man C,et al.NEL-like molecule-1-modified bone marrow mesenchymal stem cells/poly lactic-co-glycolic acid composite improves repair of large osteochondral defects in mandibular condyle. Osteoarthritis Cartilage.2011;19(6):743-750.
[35]陈明,张宇,倪龙兴. nell-1基因直接体内转染修复犬下颌骨的缺损[J].医学争鸣,2007,28(13):1211-1213.
[36]胡镜宙. Nell-1基因修饰的组织工程化骨修复颌骨缺损的实验研究[D].上海:上海交通大学, 2007.
[37]Kwak J,Zara JN,Chiang M,et al.NELL-1 Injection Maintains Long-Bone Quantity and Quality in an Ovariectomy-Induced Osteoporotic Senile Rat Model. Tissue Eng Part A. 2013;19(3-4):426-436.
[38]Li W,Zara JN,Siu RK,et al.Nell-1 enhances bone regeneration in a rat critical-sized femoral segmental defect model. Plast Reconstr Surg. 2011;127(2):580-587.
[39]Xue J,Peng J,Yuan M,et al.NELL1 promotes high-quality bone regeneration in rat femoral distraction osteogenesis model.Bone.2011; 48(3):485.
[40]Zhu S,Song D,Jiang X,et al.Combined effects of recombinant human BMP-2 and Nell-1 on bone regeneration in rapid distraction osteogenesis of rabbit tibia. Injury. 2011;42(12):1467-1473.
[41]Siu RK,Zara JN,Hou Y,et al.NELL-1 Promotes Cartilage Regeneration in an In Vivo Rabbit Model.Tissue Engineering Part A.2012;18(3-4):252.
[42]邹俊. Nell-1基因诱导大鼠脊柱后外侧融合的实验研究[D].苏州:苏州大学, 2007.
[43]James AW,Shen J,Tsuei R,et al.NELL-1 induces Sca-1+mesenchymal progenitor cell expansion in models of bone maintenance and repair. JCI Insight.2017;2(12).pii:92573.
[44]Lu SS,Zhang X,Soo C,et al.The osteoinductive properties of Nell-1 in a rat spinal fusion model. 2007;7(1):50-60.
[45]Siu RK,Lu SS,Li W,et al.Nell-1 protein promotes bone formation in a sheep spinal fusion model. Tissue Engineering Part A.2011;17(7-8):1123.
[46]Lee S,Zhang X,Shen J,et al.hPSCs and NELL-1 Synergistically Enhance Spinal Fusion in Osteoporotic Rats.Stem Cells.2015;33(10):3158.
[47]Yuan W,James AW,Asatrian G,et al.NELL-1 based demineralized bone graft promotes rat spine fusion as compared to commercially available BMP-2 product. J Orthop Sci. 2013;18(4):646-657.
[48]郭旭.Ad-GFP-NELL1对聚乙烯颗粒致颅骨骨溶解的防治作用[D].北京:军医进修学院解放军总医院,2012.
[49]郭旭,彭江,王玉,等.腺病毒介导NELL1促进骨溶解后的高质量骨再生[J].中国矫形外科杂志,2012,20(9):834-837.
[50]James AW,Shen J,Zhang X,et al.NELL-1 in the treatment of osteoporotic bone loss.2015;6(Suppl 6):7362.
[2]Wang W,Yeung K W K. Bone grafts and biomaterials substitutes for bone defect repair:Areview. Bioactive Materials.2017;2(4):224-247.
[3]Arealis G,Nikolaou VS.Bone printing:new frontiers in the treatment of bone defects. Injury.2015;46 Suppl 8:S20-22.
[4]Yu X,Tang X,Gohil SV, et al.Biomaterials for Bone Regenerative Engineering.Advanced Healthcare Materials.2015;4(9):1268.
[5]张明磊,宋显吉,尹若峰,等.神经源性表皮生长因子样分子-1局部植入促进大鼠长骨干骨折愈合的研究[J].中华实验外科杂志, 2015,32(9):2211-2213.
[6]周海华,李祖兵. Nel样1型分子对成骨细胞分化的分子调控机制[J].国际口腔医学杂志,2010, 37(2):166-169.
[7]Watanabe TK.Cloning and characterization of two novel human cDNAs(NELL1 and NELL2)encoding proteins with six EGF-like repeats.Genomics.1996;38(3):273-276.
[8]万林子,金晗,吴熙凤,等.脂质体介导NELL1基因对脂肪干细胞影响的体外研究[J].现代口腔医学杂志, 2015(3):161-165.
[9]Smith B, Goldstein T, Ekstein C.Biologic adjuvants and bone:current use in orthopedic surgery. Curr Rev Musculoskelet Med.2015;8(2):193-199.
[10]Ting K,Vastardis H,Mulliken JB,et al.Human NELL-1 expressed in unilateral coronal synostosis. J Bone Miner Res.1999;14(1):80-89.
[11]Zhang X,Kuroda S,Carpenter D,et al.Craniosynostosis in transgenic mice overexpressing Nell-1. J Clin Invest. 2002;110(6):861-870.
[12]Zhang X,Carpenter D,Bokui N,et al.Overexpression of Nell-1, a craniosynostosis. J Bone Miner Res. 2003;18(12):2126-2134.
[13]Zhang X, Kang T, Bessette C M, et al. Nell-1, a key Functional Mediator of Runx2, Partially Rescues Calvarial Defects inRunx2+/-Mice.J Bone Miner Res.2011;26(4):777-791.
[14]Zhang X,Péault B,Chen W,et al.The Nell-1 growth factor stimulates bone formation by purified human perivascular cells.Tissue Engineering Part A.2011;17(19-20):2497.
[15]Desai J,Shannon ME,Johnson MD,et al.Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. Human Molecular Genetics.2006;15(8):1329.
[16]Aghaloo T,Cowan CM,Chou YF,et al.Nell-1-induced bone regeneration in calvarial defects.Am J Pathol. 2006;169(3):903-915.
[17]胡镜宙,蒋欣泉,张志愿,等.实时定量PCR检测Nel样I型分子基因对大鼠骨髓基质细胞成骨相关基因表达的影响[J].中国口腔颌面外科杂志,2008, 6(1):48-53.
[18]Fahmygarcia S,Van DM,Wittebuoma J,et al.Nell-1, HMGB1 and CCN2 enhance migration and vasculogenesis, but not osteogenic differentiation compared to BMP2. Tissue Eng Part A. 2018;24(3-4):207-218
[19]Li G,Liu J,Wang Y,et al.LNGFR targets the Wnt/β-catenin pathway and promotes the osteogenic differentiation in rat ectomesenchymal stem cells.Sci Rep.2017;7(1):11021.
[20]Shen J,James AW,Chung J,et al.NELL-1 promotes cell adhesion and differentiation via Integrinβ1. J Cell Biochem. 2012;113(12):3620-3608.
[21]Shen J,James AW,Zhang X,et al.Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2. Am J Pathol. 2016;186(2):419-434.
[22]张弘,姚宇,孙佳栋,等. NELL-1调控RUNX2的P1启动子诱导成骨分化[J].中华口腔医学研究杂志(电子版), 2017, 11(4):197-203.
[23]Li CS,Zhang X,Péault B,et al.Accelerated Chondrogenic Differentiation of Human Perivascular Stem Cells with NELL-1.Tissue Eng Part A.2016;22(3-4):272-285
[24]Mishra R,Sefcik R,Bishop T,et al.Proliferation and Osteogenic Differentiation of Human Mesenchymal Stem Cells on Poly(propylene fumarate)Tissue Engineering Scaffolds[C]//Osuwmc Trainee Research Day. 2015.
[25]Cowan CM,Zhang X,James AW,et al.NELL-1 increases pre-osteoblast mineralization using both phosphate transporter Pit1 and Pit2. Biochem Biophys Res Commun.2012;422(3):351-357.
[26]Liu M,Wang Q,Tang R,et al.Nel-like Molecule 1 Contributes to the Odontoblastic Differentiation of Human Dental Pulp Cells. J Endod.2016;42(1):95-100.
[27]Lee M,Siu RK,Ting K,et al.Effect of Nell-1 delivery on chondrocyte proliferation and cartilaginous extracellular matrix deposition.Tissue Eng Part A.2010;16(5):1791-1800.
[28]James AW,Pan A,Chiang M,et al.A new function of Nell-1 protein in repressing adipogenic differentiation. Biochem Biophys Res Commun.2011;411(1):126-131.
[29]秦雪嫣,赵华翔,张倩,等. NELL-1:高效特异的新型生长因子[J].北京大学学报(医学版),2016,48(2):380-383.
[30]Shen J,James AW,Zara JN,et al.BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1.Tissue Engineering Part A.2013;19(21-22):2390.
[31]郭旭,彭江,王玉,等.腺病毒介导的NELL1基因对小鼠成骨细胞增殖分化的影响[J].解放军医学院学报,2012,33(5):509-511.
[32]陈微微. NELL-1蛋白对小鼠ATDC5细胞软骨分化的调控机制和对人血管周细胞成骨分化作用的研究[D].杭州:浙江大学, 2011.
[33]Lee S, Wang C, Pan HC,et al.Combining Smoothened Agonist(SAG)and NEL-like protein-1(NELL-1)Enhances Bone Healing.Plast Reconstr Surg.2017;139(6):1385-1396
[34]Zhu S,Zhang B,Man C,et al.NEL-like molecule-1-modified bone marrow mesenchymal stem cells/poly lactic-co-glycolic acid composite improves repair of large osteochondral defects in mandibular condyle. Osteoarthritis Cartilage.2011;19(6):743-750.
[35]陈明,张宇,倪龙兴. nell-1基因直接体内转染修复犬下颌骨的缺损[J].医学争鸣,2007,28(13):1211-1213.
[36]胡镜宙. Nell-1基因修饰的组织工程化骨修复颌骨缺损的实验研究[D].上海:上海交通大学, 2007.
[37]Kwak J,Zara JN,Chiang M,et al.NELL-1 Injection Maintains Long-Bone Quantity and Quality in an Ovariectomy-Induced Osteoporotic Senile Rat Model. Tissue Eng Part A. 2013;19(3-4):426-436.
[38]Li W,Zara JN,Siu RK,et al.Nell-1 enhances bone regeneration in a rat critical-sized femoral segmental defect model. Plast Reconstr Surg. 2011;127(2):580-587.
[39]Xue J,Peng J,Yuan M,et al.NELL1 promotes high-quality bone regeneration in rat femoral distraction osteogenesis model.Bone.2011; 48(3):485.
[40]Zhu S,Song D,Jiang X,et al.Combined effects of recombinant human BMP-2 and Nell-1 on bone regeneration in rapid distraction osteogenesis of rabbit tibia. Injury. 2011;42(12):1467-1473.
[41]Siu RK,Zara JN,Hou Y,et al.NELL-1 Promotes Cartilage Regeneration in an In Vivo Rabbit Model.Tissue Engineering Part A.2012;18(3-4):252.
[42]邹俊. Nell-1基因诱导大鼠脊柱后外侧融合的实验研究[D].苏州:苏州大学, 2007.
[43]James AW,Shen J,Tsuei R,et al.NELL-1 induces Sca-1+mesenchymal progenitor cell expansion in models of bone maintenance and repair. JCI Insight.2017;2(12).pii:92573.
[44]Lu SS,Zhang X,Soo C,et al.The osteoinductive properties of Nell-1 in a rat spinal fusion model. 2007;7(1):50-60.
[45]Siu RK,Lu SS,Li W,et al.Nell-1 protein promotes bone formation in a sheep spinal fusion model. Tissue Engineering Part A.2011;17(7-8):1123.
[46]Lee S,Zhang X,Shen J,et al.hPSCs and NELL-1 Synergistically Enhance Spinal Fusion in Osteoporotic Rats.Stem Cells.2015;33(10):3158.
[47]Yuan W,James AW,Asatrian G,et al.NELL-1 based demineralized bone graft promotes rat spine fusion as compared to commercially available BMP-2 product. J Orthop Sci. 2013;18(4):646-657.
[48]郭旭.Ad-GFP-NELL1对聚乙烯颗粒致颅骨骨溶解的防治作用[D].北京:军医进修学院解放军总医院,2012.
[49]郭旭,彭江,王玉,等.腺病毒介导NELL1促进骨溶解后的高质量骨再生[J].中国矫形外科杂志,2012,20(9):834-837.
[50]James AW,Shen J,Zhang X,et al.NELL-1 in the treatment of osteoporotic bone loss.2015;6(Suppl 6):7362.