NELL-1蛋白促成骨研究现状
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摘要
NELL-1具有特异性促成骨能力,局部注射可修复骨缺损,已经在修复重建外科得到了广泛的应用,聚乙二醇化的NELL-1全身应用可逆转骨质疏松,且无全身炎症反应及毒性反应,是一种潜在的治疗骨质疏松的药物。NELL-1蛋白聚乙二醇化产物NELL-PEG具有很强成骨活性及治疗骨质疏松的潜在价值。本文总结近年来NELL-1蛋白在促成骨方面的研究进展,以及NELL-PEG抗骨质疏松症的机理。
NELL-1 has specific osteogenic potential, and local injection of it can repair bone defects. It has been widely used in reconstructive surgery. Pegylated NELL-1 systemic application could reverse osteoporosis without systemic inflammation and toxic reactions. Therefore, it is a potential drug for the treatment of osteoporosis, especially NELL-PEG, a NELL-1 pegylated product, which proved strong osteogenic activity and potential value in the treatment of osteoporosis. This paper aims to summarize the research progress on NELL-1 protein in promoting bone formation in recent years, and present the anti-osteoporosis mechanism of NELL-PEG.
NELL-1 has specific osteogenic potential, and local injection of it can repair bone defects. It has been widely used in reconstructive surgery. Pegylated NELL-1 systemic application could reverse osteoporosis without systemic inflammation and toxic reactions. Therefore, it is a potential drug for the treatment of osteoporosis, especially NELL-PEG, a NELL-1 pegylated product, which proved strong osteogenic activity and potential value in the treatment of osteoporosis. This paper aims to summarize the research progress on NELL-1 protein in promoting bone formation in recent years, and present the anti-osteoporosis mechanism of NELL-PEG.
引文
[1]Matsuhashi S,Noji S,Koyama E,et al.New gene,nel,encoding a M(r)93 K protein with EGF-like repeats is strongly expressed in neural tissues of early stage chick embryos[J].Developmental Dynamics,2010,203(2):212-222.
[2]Watanabe TK,Katagiri T,Suzuki M,et al.Cloning and characterization of two novel human cDNAs(NELL1 and NELL2)encoding proteins with six EGF-like repeats[J].Genomics,1996,38(3):273-276.
[3]Ting K,Vastardis H,Mulliken JB,et al.Human NELL-1 expressed in unilateral coronal synostosis[J].J Bone Mineral Res,2010,14(1):80-89.
[4]Pakvasa M,Alverdy A,Mostafa S,et al.Neural EGF-Like protein1(NELL-1):signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine[J].Genes Dis,2017,4(3):127-137.
[5]Zhang X,Zara J,Siu RK,et al.The role of NELL-1,a growth factor associated with craniosynostosis,in promoting bone regeneration[J].J Dental Res,2010,89(9):865-878.
[6]Brault V,Moore R,Kutsch S,et al.Inactivation of the(β)-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development[J].Development,2001,128(8):1253.
[7]Shen J,James AW,Chung J,et al.NELL-1 promotes cell adhesion and differentiation via Integrinβ1[J].J Cellular Biochem,2012,113(12):3620-3628.
[8]Bokui N,Otani T,Igarashi K,et al.Involvement of MAPK signaling molecules and Runx2 in the NELL1-induced osteoblastic differentiation[J].FEBS Letters,2008,582(2):365-371.
[9]Lu SS,Zhang X,Soo C,et al.The osteoinductive properties of Nell-1 in a rat spinal fusion model[J].Spine J,2007,7(1):50-60.
[10]Cowan CM,Jiang X,Hsu T,et al.Synergistic effects of Nell-1 and BMP-2 on the osteogenic differentiation of myoblasts[J].J Bone Mineral Res,2010,22(6):918-930.
[11]Karsenty G.Transcriptional control of skeletogenesis[J].Annu Rev Genomics Hum Genet,2008,9(9):183-196.
[12]Chen F,Zhang X,Sun S,et al.NELL-1,an osteoinductive factor,is a direct transcriptional target of Osterix[J].Plos One,2011,6(9):e24638.
[13]Kim HK,Randall TS,Bian H,et al.ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoral epiphysis in immature pig[J].J Bone Joint Surg Am,2005,87(3):550-557.
[14]Fan M,Jiang WX,Wang AY,et al.Combined effects of NEL-like type 1 gene and zoledronate in preventing collapse of the femoral head[J].Acta Acad Med Sinicae,2013,35(5):553-60.
[15]Korovessis P,Koureas G,Zacharatos S,et al.Correlative radiological,self-assessment and clinical analysis of evolution in instrumented dorsal and lateral fusion for degenerative lumbar spine disease.Autograft versus coralline hydroxyapatite[J].Eur Spine J,2005,14(7):630-638.
[16]D'Ippolito G,Schiller PC,Ricordi C,et al.Age related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow[J].J Bone Mineral Res,2010,14(7):1115-1122.
[17]Takahata M,Ito M,Abe Y,et al.The effect of anti-resorptive therapies on bone graft healing in an ovariectomized rat spinal arthrodesis model[J].Bone,2008,43(6):1057-1066.
[18]Nakao S,Minamide A,Kawakami M,et al.The influence of alendronate on spine fusion in an osteoporotic animal model[J].Spine,2011,36(18):1446-1452.
[19]Miyazaki M,Tsumura H,Wang JC,et al.An update on bone substitutes for spinal fusion[J].Eur Spine J,2009,18(6):783-799.
[20]Kwak J,Zara J N,Chiang M,et al.NELL-1 injection maintains long-bone quantity and quality in an ovariectomy-induced osteoporotic senile rat model[J].Tissue Eng Part A,2013,19(3-4):426-436.
[21]Chung CG,James AW,Asatrian G,et al.Human perivascular stem cell-based bone graft substituteinduces rat spinal fusion[J].Stem Cells Translational Med,2014;3:1231-1241.
[22]Lee S,Zhang X,Shen J,et al.Brief report:human perivascular stem cells and nel like Protein 1 synergistically enhance spinal fusion in osteoporotic rats[J].Stem Cells,2015,33(10):3158-3163.
[23]Zhang X,Péault B,Chen W,et al.The Nell-1 growth factor stimulates bone formation by purified human perivascular cells[J].Tissue Eng Part A,2011,17(19-20):2497.
[24]Askarinam A,James AW,Zara JN,et al.Human perivascular stem cells show enhanced osteogenesis and vasculogenesis with Nellike molecule I protein[J].Tissue Engin Part A,2013,19(11-12):1386-1397.
[25]Fahmygarcia S,Van DM,Wittebuoma J,et al.Nell-1,HMGB1and CCN2 enhance migration and vasculogenesis,but not osteogenic differentiation compared to BMP2[J].Tissue Eng Part A,2017,2017(3-4).
[26]Vaidya R,Weir R,Sethi A,et al.Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence[J].J Bone Joint Surg Br,2007,89(3):342.
[27]曾宪铁,张国骏.原发性骨质疏松症的中医药研究进展[J].中国矫形外科杂志,2008,16(3):191-193.
[28]陆声,常山.骨质疏松药物治疗的新进展[J].中国矫形外科杂志,2001,8(9):912-915.
[29]Becker DJ,Kilgore ML,Morrisey MA.The societal burden of osteoporosis[J].Curr Rheumatol Rep,2007,40(6):1602-1609.
[30]Wing MLR,Abbah SA,Ming W,et al.Polyelectrolyte complex for heparin binding domain osteogenic growth factor delivery[J/OL].JVis Exp,2016,2016(114),DOI:10.3791/54202.
[31]Zhang Y,Velasco O,Zhang X,et al.Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy[J].Biomaterials,2014,35(24):6614-6621.
[32]Kwak JH,Zhang YL.Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration[J].Biomaterials,2015,57(1):73-83.
[33]James AW,Shen J,Tsuei R,et al.NELL-1 induces Sca-1+mesenchymal progenitor cell expansion in models of bone maintenance and repair[J].Jci Insight,2017,2(12):92573.
[34]Tanjaya J,Zhang Y,Lee S,et al.Efficacy of intraperitoneal administration of PEGylated NELL-1 for bone formation[J].Bioresearch Open Access,2016,5(1):159-170.
[35]Shen J,James AW,Zara JN,et al.BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1[J].Tissue Eng Part A,2013,19(21-22):2390-2401.
[36]Ransom RC,Longaker MT.Discussion:combining smoothened agonist and NEL-Like protein-1 enhances bone healing[J].Plastic Reconstr Surg,2017,139(6):1397-1398.
[2]Watanabe TK,Katagiri T,Suzuki M,et al.Cloning and characterization of two novel human cDNAs(NELL1 and NELL2)encoding proteins with six EGF-like repeats[J].Genomics,1996,38(3):273-276.
[3]Ting K,Vastardis H,Mulliken JB,et al.Human NELL-1 expressed in unilateral coronal synostosis[J].J Bone Mineral Res,2010,14(1):80-89.
[4]Pakvasa M,Alverdy A,Mostafa S,et al.Neural EGF-Like protein1(NELL-1):signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine[J].Genes Dis,2017,4(3):127-137.
[5]Zhang X,Zara J,Siu RK,et al.The role of NELL-1,a growth factor associated with craniosynostosis,in promoting bone regeneration[J].J Dental Res,2010,89(9):865-878.
[6]Brault V,Moore R,Kutsch S,et al.Inactivation of the(β)-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development[J].Development,2001,128(8):1253.
[7]Shen J,James AW,Chung J,et al.NELL-1 promotes cell adhesion and differentiation via Integrinβ1[J].J Cellular Biochem,2012,113(12):3620-3628.
[8]Bokui N,Otani T,Igarashi K,et al.Involvement of MAPK signaling molecules and Runx2 in the NELL1-induced osteoblastic differentiation[J].FEBS Letters,2008,582(2):365-371.
[9]Lu SS,Zhang X,Soo C,et al.The osteoinductive properties of Nell-1 in a rat spinal fusion model[J].Spine J,2007,7(1):50-60.
[10]Cowan CM,Jiang X,Hsu T,et al.Synergistic effects of Nell-1 and BMP-2 on the osteogenic differentiation of myoblasts[J].J Bone Mineral Res,2010,22(6):918-930.
[11]Karsenty G.Transcriptional control of skeletogenesis[J].Annu Rev Genomics Hum Genet,2008,9(9):183-196.
[12]Chen F,Zhang X,Sun S,et al.NELL-1,an osteoinductive factor,is a direct transcriptional target of Osterix[J].Plos One,2011,6(9):e24638.
[13]Kim HK,Randall TS,Bian H,et al.ibandronate for prevention of femoral head deformity after ischemic necrosis of the capital femoral epiphysis in immature pig[J].J Bone Joint Surg Am,2005,87(3):550-557.
[14]Fan M,Jiang WX,Wang AY,et al.Combined effects of NEL-like type 1 gene and zoledronate in preventing collapse of the femoral head[J].Acta Acad Med Sinicae,2013,35(5):553-60.
[15]Korovessis P,Koureas G,Zacharatos S,et al.Correlative radiological,self-assessment and clinical analysis of evolution in instrumented dorsal and lateral fusion for degenerative lumbar spine disease.Autograft versus coralline hydroxyapatite[J].Eur Spine J,2005,14(7):630-638.
[16]D'Ippolito G,Schiller PC,Ricordi C,et al.Age related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow[J].J Bone Mineral Res,2010,14(7):1115-1122.
[17]Takahata M,Ito M,Abe Y,et al.The effect of anti-resorptive therapies on bone graft healing in an ovariectomized rat spinal arthrodesis model[J].Bone,2008,43(6):1057-1066.
[18]Nakao S,Minamide A,Kawakami M,et al.The influence of alendronate on spine fusion in an osteoporotic animal model[J].Spine,2011,36(18):1446-1452.
[19]Miyazaki M,Tsumura H,Wang JC,et al.An update on bone substitutes for spinal fusion[J].Eur Spine J,2009,18(6):783-799.
[20]Kwak J,Zara J N,Chiang M,et al.NELL-1 injection maintains long-bone quantity and quality in an ovariectomy-induced osteoporotic senile rat model[J].Tissue Eng Part A,2013,19(3-4):426-436.
[21]Chung CG,James AW,Asatrian G,et al.Human perivascular stem cell-based bone graft substituteinduces rat spinal fusion[J].Stem Cells Translational Med,2014;3:1231-1241.
[22]Lee S,Zhang X,Shen J,et al.Brief report:human perivascular stem cells and nel like Protein 1 synergistically enhance spinal fusion in osteoporotic rats[J].Stem Cells,2015,33(10):3158-3163.
[23]Zhang X,Péault B,Chen W,et al.The Nell-1 growth factor stimulates bone formation by purified human perivascular cells[J].Tissue Eng Part A,2011,17(19-20):2497.
[24]Askarinam A,James AW,Zara JN,et al.Human perivascular stem cells show enhanced osteogenesis and vasculogenesis with Nellike molecule I protein[J].Tissue Engin Part A,2013,19(11-12):1386-1397.
[25]Fahmygarcia S,Van DM,Wittebuoma J,et al.Nell-1,HMGB1and CCN2 enhance migration and vasculogenesis,but not osteogenic differentiation compared to BMP2[J].Tissue Eng Part A,2017,2017(3-4).
[26]Vaidya R,Weir R,Sethi A,et al.Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence[J].J Bone Joint Surg Br,2007,89(3):342.
[27]曾宪铁,张国骏.原发性骨质疏松症的中医药研究进展[J].中国矫形外科杂志,2008,16(3):191-193.
[28]陆声,常山.骨质疏松药物治疗的新进展[J].中国矫形外科杂志,2001,8(9):912-915.
[29]Becker DJ,Kilgore ML,Morrisey MA.The societal burden of osteoporosis[J].Curr Rheumatol Rep,2007,40(6):1602-1609.
[30]Wing MLR,Abbah SA,Ming W,et al.Polyelectrolyte complex for heparin binding domain osteogenic growth factor delivery[J/OL].JVis Exp,2016,2016(114),DOI:10.3791/54202.
[31]Zhang Y,Velasco O,Zhang X,et al.Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy[J].Biomaterials,2014,35(24):6614-6621.
[32]Kwak JH,Zhang YL.Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration[J].Biomaterials,2015,57(1):73-83.
[33]James AW,Shen J,Tsuei R,et al.NELL-1 induces Sca-1+mesenchymal progenitor cell expansion in models of bone maintenance and repair[J].Jci Insight,2017,2(12):92573.
[34]Tanjaya J,Zhang Y,Lee S,et al.Efficacy of intraperitoneal administration of PEGylated NELL-1 for bone formation[J].Bioresearch Open Access,2016,5(1):159-170.
[35]Shen J,James AW,Zara JN,et al.BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1[J].Tissue Eng Part A,2013,19(21-22):2390-2401.
[36]Ransom RC,Longaker MT.Discussion:combining smoothened agonist and NEL-Like protein-1 enhances bone healing[J].Plastic Reconstr Surg,2017,139(6):1397-1398.