分子信号通路及细胞层面的骨折愈合机制
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摘要
背景:骨不连和骨折延迟愈合不仅对个人和家庭造成了极大的困扰,对整个社会也会带来巨大的经济损失。而最佳的骨折治疗需要了解骨折愈合的复杂生理过程。目的:综述国内外相关文献,通过研究和对比骨折愈合机制,为临床诊断、治疗提供新的思路。方法:中文以"骨折愈合,骨折不愈合,炎症,信号通路,破骨细胞,成骨细胞,骨形态发生蛋白,Wnt,甲状旁腺激素,Hedgehog"检索CNKI、万方、维普数据库;英文以"Fracturehealing,Nonunion,Inflammation, Signaling pathways, Osteoclast,Osteoblast,BMP,Wnt,Hedgehog,PTH"检索PubMed数据库,收录与骨折愈合机制有关的分子信号通路和基因细胞研究相关的文献报道,并排除重复性研究,按照纳入和排除标准对文献进行筛选,共纳入46篇文章进行综述分析。结果与结论:(1)通过从炎症阶段、信号通路、细胞3个方面对骨折愈合机制进行综述讨论,发现临床和早期科研之间的矛盾(如副反应)能在更深层次的研究中得到统一;(2)但由于骨折愈合机制过于复杂,现在的研究结果并不足以解开所有临床问题;(3)不同分子之间相互影响,难以找到具有临床意义可以用于早期骨不连临床诊断的标志物;(4)需要研发更加精细的实验设备和设计更严密的科研方案,服务临床;(5)但是针对目前的科研结果,可以考虑配合仿生骨信号递送系统,使原本孤立、平面、静止的研究结果具有三维动态性更符合临床实际的治疗需求,这是下一步考虑的事情。
BACKGROUND: Nonunion and delayed union of fractures not only cause great troubles to individuals and families, but bring huge financial burden to the society. The optimal fracture treatment requires understanding of the complex physiological process of fracture healing.OBJECTIVE: To explore and compare the fracture healing mechanism by reviewing the relevant literature, so as to provide new idea for clinical diagnosis and treatment.METHODS: CNKI, WanFang, VIP and PubMed databases were retrieved with the keywords of "fracture healing, nonunion, inflammation,signaling pathways, osteoclasts, osteoblast, BMP, Wnt, Hedgehog, PTH" in Chinese and English, respectively. The articles concerning the molecular/signaling pathway/cell of fracture healing mechanism, the repetitive studies were excluded, and finally 46 eligible articles were enrolled for analysis.RESULTS AND CONCLUSION:(1) By summarizing and discussing the mechanism of fracture healing from the aspects of inflammation stage, signal pathway and cell, we found that the contradiction between clinical and early scientific research(such as adverse reactions) can be unified in deep research.(2) However, the current research results cannot solve all clinical problems due to the complicated mechanisms of fracture healing.(3) The interaction between different molecules makes it difficult to find a clinically significant marker for the clinical diagnosis of early nonunion.(4) It is necessary to develop more sophisticated experimental equipment and design more rigorous scientific research programs to serve the clinical practice.(5) However, according to the current research results, we can consider cooperating with biomimetic delivery of signals for bone tissue engineering to make the original isolated, planar and static research results have three-dimensional dynamics more in line with the clinical treatment needs, which is the future direction.
BACKGROUND: Nonunion and delayed union of fractures not only cause great troubles to individuals and families, but bring huge financial burden to the society. The optimal fracture treatment requires understanding of the complex physiological process of fracture healing.OBJECTIVE: To explore and compare the fracture healing mechanism by reviewing the relevant literature, so as to provide new idea for clinical diagnosis and treatment.METHODS: CNKI, WanFang, VIP and PubMed databases were retrieved with the keywords of "fracture healing, nonunion, inflammation,signaling pathways, osteoclasts, osteoblast, BMP, Wnt, Hedgehog, PTH" in Chinese and English, respectively. The articles concerning the molecular/signaling pathway/cell of fracture healing mechanism, the repetitive studies were excluded, and finally 46 eligible articles were enrolled for analysis.RESULTS AND CONCLUSION:(1) By summarizing and discussing the mechanism of fracture healing from the aspects of inflammation stage, signal pathway and cell, we found that the contradiction between clinical and early scientific research(such as adverse reactions) can be unified in deep research.(2) However, the current research results cannot solve all clinical problems due to the complicated mechanisms of fracture healing.(3) The interaction between different molecules makes it difficult to find a clinically significant marker for the clinical diagnosis of early nonunion.(4) It is necessary to develop more sophisticated experimental equipment and design more rigorous scientific research programs to serve the clinical practice.(5) However, according to the current research results, we can consider cooperating with biomimetic delivery of signals for bone tissue engineering to make the original isolated, planar and static research results have three-dimensional dynamics more in line with the clinical treatment needs, which is the future direction.
引文
[1]Einhorn TA,Gerstenfeld LC.Fracture healing:mechanisms and interventions.Nat Rev Rheumatol.2015;11(1):45-54.
[2]Claes L,Recknagel S,Ignatius A.Fracture healing under healthy and inflammatory conditions.Nat Rev Rheumatol.2012;8(3):133-143.
[3]Shiu HT,Leung PC,Ko CH.The roles of cellular and molecular components of a hematoma at early stage of bone healing.J Tissue Eng Regen Med.2018;12(4):e1911-e1925.
[4]Reinke S,Geissler S,Taylor WR,et al.Terminally differentiated CD8?T cells negatively affect bone regeneration in humans.Sci Transl Med.2013;5(177):177ra36.
[5]Dai Y,Li X,Wu R,et al.Macrophages of different phenotypes influence the migration of bmscs in plga scaffolds with different pore size.Biotechnol J.2018;13(1).doi:10.1002/biot.201700297.
[6]Chan JK,Glass GE,Ersek A,et al.Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.EMBO Mol Med.2015;7(5):547-561.
[7]Xing Z,Lu C,Hu D,et al.Multiple roles for CCR2 during fracture healing.Dis Model Mech.2010;3(7-8):451-458.
[8]Wang D,Gilbert JR,Cray JJ,et al.Accelerated calvarial healing in mice lacking Toll-like receptor 4.PLoS ONE.2012;7(10):e46945.
[9]Kalyan S.It may seem inflammatory,but some T cells are innately healing to the bone.J Bone Miner Res.2016;31(11):1997-2000.
[10]Glass GE,Chan JK,Freidin A,et al.TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells.Proc Natl Acad Sci USA.2011;108(4):1585-1590.
[11]Gerstenfeld LC,Cho TJ,Kon T,et al.Impaired fracture healing in the absence of TNF-alpha signaling:the role of TNF-alpha in endochondral cartilage resorption.J Bone Miner Res.2003;18(9):1584-1592.
[12]Ausk BJ,Gross TS,Bain SD.Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation.Clin Orthop Relat Res.2015;473(9):2825-2830.
[13]Lim JC,Ko KI,Mattos M,et al.TNFαcontributes to diabetes impaired angiogenesis in fracture healing.Bone.2017;99:26-38.
[14]Lu LY,Loi F,Nathan K,et al.Pro-inflammatory M1 macrophages promote Osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway.J Orthop Res.2017;35(11):2378-2385.
[15]Zhang X,Schwarz EM,Young DA,et al.Cyclooxygenase-2regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair.J Clin Invest.2002;109(11):1405-1415.
[16]Wang JH,Liu YZ,Yin LJ,et al.BMP9 and COX-2 form an important regulatory loop in BMP9-induced osteogenic differentiation of mesenchymal stem cells.Bone.2013;57(1):311-321.
[17]Brazil DP,Church RH,Surae S,et al.BMP signalling:agony and antagony in the family.Trends Cell Biol.2015;25(5):249-264.
[18]Oryan A,Alidadi S,Moshiri A,et al.Bone morphogenetic proteins:a powerful osteoinductive compound with non-negligible side effects and limitations.Biofactors.2014;40(5):459-481.
[19]Solloway MJ,Dudley AT,Bikoff EK,et al.Mice lacking Bmp6function.Dev Genet.1998;22(4):321-339.
[20]Tsuji K,Bandyopadhyay A,Harfe BD,et al.BMP2 activity,although dispensable for bone formation,is required for the initiation of fracture healing.Nat Genet.2006;38(12):1424-1429.
[21]Tsuji K,Cox K,Bandyopadhyay A,et al.BMP4 is dispensable for skeletogenesis and fracture-healing in the limb.J Bone Joint Surg Am.2008;90 Suppl 1:14-18.
[22]Tsuji K,Cox K,Gamer L,et al.Conditional deletion of BMP7from the limb skeleton does not affect bone formation or fracture repair.J Orthopa Res.2010;28(3):384-389.
[23]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 of20p12 deletions.Am J Hum Genet.2017;101(6):985-994.
[24]Ellies DL,Viviano B,Mccarthy J,et al.Bone density ligand,Sclerostin,directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity.J Bone Miner Res.2010;21(11):1738-1749.
[25]Gong Y,Slee RB,Fukai N,et al.LDL receptor-related protein5(LRP5)affects bone accrual and eye development.Cell.2001;107(4):513-523.
[26]Niziolek PJ,MacDonald BT,Kedlaya R,et al.High bone mass-causing mutant lrp5 receptors are resistant to endogenous inhibitors in vivo.J Bone Miner Res.2015;30(10):1822-1830.
[27]Yan C,Whetstone HC,Lin AC,et al.Beta-catenin signaling plays a disparate role in different phases of fracture repair:implications for therapy to improve bone healing.Plos Med.2007;4(7):e249.
[28]Jin H,Wang B,Li J,et al.Anti-DKK1 antibody promotes bone fracture healing through activation ofβ-catenin signaling.Bone.2015;71:63-75.
[29]Long F,Chung UI,Ohba S,et al.Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton.Development.2004;131(6):1309-1318.
[30]Baht GS,Silkstone D,Nadesan P,et al.Activation of hedgehog signaling during fracture repair enhances osteoblasticdependent matrix formation.J Orthop Res.2014;32(4):581-586.
[31]Kazmers NH,McKenzie JA,Shen TS,et al.Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing.Bone.2015;81:524-532.
[32]Esbrit P,Alcaraz MJ.Current perspectives on parathyroid hormone(PTH)and PTH-related protein(PTHrP)as bone anabolic therapies.Biochem Pharmacol.2013;85(10):1417-1423.
[33]Ren Y,Bo L,Feng Y,et al.Endogenous PTH Deficiency Impairs Fracture Healing and Impedes the Fracture-Healing Efficacy of Exogenous PTH(1-34).Plos One.2011;6(6):e23060.
[34]Esen E,Lee SY,Wice BM,et al.PTH Promotes Bone Anabolism by Stimulating Aerobic Glycolysis via IGFSignaling.J Bone Miner Res.2015;30(11):1959-1968.
[35]Grosso MJ,Courtland HW,Yang X,et al.Intermittent PTHadministration and mechanical loading are anabolic for periprosthetic cancellous bone.J Orthop Res.2015;33(2):163-173.
[36]Yukata K,Kanchiku T,Egawa H,et al.Continuous infusion of PTH delayed fracture healing in mice.Sci Rep.2018;8(1):13175.
[37]Bodine PV,Seestaller-Wehr L,Kharode YP,et al.Bone anabolic effects of parathyroid hormone are blunted by deletion of the Wnt antagonist secreted frizzled-related protein-1.J Cell Physiol.2007;210(2):352-357.
[38]Guo J,Liu M,Yang D,et al.Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation.Cell Metab.2010;11(2):161-171.
[39]Sims NA,Civitelli R.Cell-cell signaling:broadening our view of the basic multicellular unit.Calcif Tissue Int.2014;94:2-3.
[40]Kenichi N.Cellular communications in bone homeostasis and repair.Cell Mol Life Sci.2010;67(23):4001-4009.
[41]Ren H,Ren H,Li X,et al.Effects of intermedin on proliferation,apoptosis and the expression of OPG/RANKL/M-CSF in the MC3T3-E1 osteoblast cell line.Mol Med Rep.2015;12(5):113-117.
[42]王丽美.ephrinB2-EphB4正向信号介导的TNF-α调控成骨细胞分化过程中的作用研究[D].济南:山东大学,2017.
[43]Forlino A,Marini JC.Osteogenes is imperfecta.Lancet.2016;387(10028):1657-1671.
[44]Marie PJ.Osteoblast dysfunctions in bone diseases:from cellular and molecular mechanisms to therapeutic strategies.Cell Mol Life Sci.2015;72(7):1347-1361.
[45]官建中,刘亚军,王照东,等.联合应用外源性TGF-β2及IGF-1对大鼠骨折愈合的影响[J].中国矫形外科杂志,2016,24(2):165-170.
[46]Sévère N,DieudonnéFX.E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis.Cell Death Dis.2013;4:e463.
[2]Claes L,Recknagel S,Ignatius A.Fracture healing under healthy and inflammatory conditions.Nat Rev Rheumatol.2012;8(3):133-143.
[3]Shiu HT,Leung PC,Ko CH.The roles of cellular and molecular components of a hematoma at early stage of bone healing.J Tissue Eng Regen Med.2018;12(4):e1911-e1925.
[4]Reinke S,Geissler S,Taylor WR,et al.Terminally differentiated CD8?T cells negatively affect bone regeneration in humans.Sci Transl Med.2013;5(177):177ra36.
[5]Dai Y,Li X,Wu R,et al.Macrophages of different phenotypes influence the migration of bmscs in plga scaffolds with different pore size.Biotechnol J.2018;13(1).doi:10.1002/biot.201700297.
[6]Chan JK,Glass GE,Ersek A,et al.Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.EMBO Mol Med.2015;7(5):547-561.
[7]Xing Z,Lu C,Hu D,et al.Multiple roles for CCR2 during fracture healing.Dis Model Mech.2010;3(7-8):451-458.
[8]Wang D,Gilbert JR,Cray JJ,et al.Accelerated calvarial healing in mice lacking Toll-like receptor 4.PLoS ONE.2012;7(10):e46945.
[9]Kalyan S.It may seem inflammatory,but some T cells are innately healing to the bone.J Bone Miner Res.2016;31(11):1997-2000.
[10]Glass GE,Chan JK,Freidin A,et al.TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells.Proc Natl Acad Sci USA.2011;108(4):1585-1590.
[11]Gerstenfeld LC,Cho TJ,Kon T,et al.Impaired fracture healing in the absence of TNF-alpha signaling:the role of TNF-alpha in endochondral cartilage resorption.J Bone Miner Res.2003;18(9):1584-1592.
[12]Ausk BJ,Gross TS,Bain SD.Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation.Clin Orthop Relat Res.2015;473(9):2825-2830.
[13]Lim JC,Ko KI,Mattos M,et al.TNFαcontributes to diabetes impaired angiogenesis in fracture healing.Bone.2017;99:26-38.
[14]Lu LY,Loi F,Nathan K,et al.Pro-inflammatory M1 macrophages promote Osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway.J Orthop Res.2017;35(11):2378-2385.
[15]Zhang X,Schwarz EM,Young DA,et al.Cyclooxygenase-2regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair.J Clin Invest.2002;109(11):1405-1415.
[16]Wang JH,Liu YZ,Yin LJ,et al.BMP9 and COX-2 form an important regulatory loop in BMP9-induced osteogenic differentiation of mesenchymal stem cells.Bone.2013;57(1):311-321.
[17]Brazil DP,Church RH,Surae S,et al.BMP signalling:agony and antagony in the family.Trends Cell Biol.2015;25(5):249-264.
[18]Oryan A,Alidadi S,Moshiri A,et al.Bone morphogenetic proteins:a powerful osteoinductive compound with non-negligible side effects and limitations.Biofactors.2014;40(5):459-481.
[19]Solloway MJ,Dudley AT,Bikoff EK,et al.Mice lacking Bmp6function.Dev Genet.1998;22(4):321-339.
[20]Tsuji K,Bandyopadhyay A,Harfe BD,et al.BMP2 activity,although dispensable for bone formation,is required for the initiation of fracture healing.Nat Genet.2006;38(12):1424-1429.
[21]Tsuji K,Cox K,Bandyopadhyay A,et al.BMP4 is dispensable for skeletogenesis and fracture-healing in the limb.J Bone Joint Surg Am.2008;90 Suppl 1:14-18.
[22]Tsuji K,Cox K,Gamer L,et al.Conditional deletion of BMP7from the limb skeleton does not affect bone formation or fracture repair.J Orthopa Res.2010;28(3):384-389.
[23]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 of20p12 deletions.Am J Hum Genet.2017;101(6):985-994.
[24]Ellies DL,Viviano B,Mccarthy J,et al.Bone density ligand,Sclerostin,directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity.J Bone Miner Res.2010;21(11):1738-1749.
[25]Gong Y,Slee RB,Fukai N,et al.LDL receptor-related protein5(LRP5)affects bone accrual and eye development.Cell.2001;107(4):513-523.
[26]Niziolek PJ,MacDonald BT,Kedlaya R,et al.High bone mass-causing mutant lrp5 receptors are resistant to endogenous inhibitors in vivo.J Bone Miner Res.2015;30(10):1822-1830.
[27]Yan C,Whetstone HC,Lin AC,et al.Beta-catenin signaling plays a disparate role in different phases of fracture repair:implications for therapy to improve bone healing.Plos Med.2007;4(7):e249.
[28]Jin H,Wang B,Li J,et al.Anti-DKK1 antibody promotes bone fracture healing through activation ofβ-catenin signaling.Bone.2015;71:63-75.
[29]Long F,Chung UI,Ohba S,et al.Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton.Development.2004;131(6):1309-1318.
[30]Baht GS,Silkstone D,Nadesan P,et al.Activation of hedgehog signaling during fracture repair enhances osteoblasticdependent matrix formation.J Orthop Res.2014;32(4):581-586.
[31]Kazmers NH,McKenzie JA,Shen TS,et al.Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing.Bone.2015;81:524-532.
[32]Esbrit P,Alcaraz MJ.Current perspectives on parathyroid hormone(PTH)and PTH-related protein(PTHrP)as bone anabolic therapies.Biochem Pharmacol.2013;85(10):1417-1423.
[33]Ren Y,Bo L,Feng Y,et al.Endogenous PTH Deficiency Impairs Fracture Healing and Impedes the Fracture-Healing Efficacy of Exogenous PTH(1-34).Plos One.2011;6(6):e23060.
[34]Esen E,Lee SY,Wice BM,et al.PTH Promotes Bone Anabolism by Stimulating Aerobic Glycolysis via IGFSignaling.J Bone Miner Res.2015;30(11):1959-1968.
[35]Grosso MJ,Courtland HW,Yang X,et al.Intermittent PTHadministration and mechanical loading are anabolic for periprosthetic cancellous bone.J Orthop Res.2015;33(2):163-173.
[36]Yukata K,Kanchiku T,Egawa H,et al.Continuous infusion of PTH delayed fracture healing in mice.Sci Rep.2018;8(1):13175.
[37]Bodine PV,Seestaller-Wehr L,Kharode YP,et al.Bone anabolic effects of parathyroid hormone are blunted by deletion of the Wnt antagonist secreted frizzled-related protein-1.J Cell Physiol.2007;210(2):352-357.
[38]Guo J,Liu M,Yang D,et al.Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation.Cell Metab.2010;11(2):161-171.
[39]Sims NA,Civitelli R.Cell-cell signaling:broadening our view of the basic multicellular unit.Calcif Tissue Int.2014;94:2-3.
[40]Kenichi N.Cellular communications in bone homeostasis and repair.Cell Mol Life Sci.2010;67(23):4001-4009.
[41]Ren H,Ren H,Li X,et al.Effects of intermedin on proliferation,apoptosis and the expression of OPG/RANKL/M-CSF in the MC3T3-E1 osteoblast cell line.Mol Med Rep.2015;12(5):113-117.
[42]王丽美.ephrinB2-EphB4正向信号介导的TNF-α调控成骨细胞分化过程中的作用研究[D].济南:山东大学,2017.
[43]Forlino A,Marini JC.Osteogenes is imperfecta.Lancet.2016;387(10028):1657-1671.
[44]Marie PJ.Osteoblast dysfunctions in bone diseases:from cellular and molecular mechanisms to therapeutic strategies.Cell Mol Life Sci.2015;72(7):1347-1361.
[45]官建中,刘亚军,王照东,等.联合应用外源性TGF-β2及IGF-1对大鼠骨折愈合的影响[J].中国矫形外科杂志,2016,24(2):165-170.
[46]Sévère N,DieudonnéFX.E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis.Cell Death Dis.2013;4:e463.