骨生长因子调控骨折愈合机制及在骨再生修复中的作用
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摘要
背景:研究发现生物复合支架载体诱导骨生长因子在骨折局部的充分表达能够有效缩减骨折愈合的时间。目的:综述国内外相关文献,总结骨生长因子调控骨折愈合机制及应用进展。方法:中文以"骨生长因子、成纤维细胞生长因子、血小板衍生生长因子、转化生长因子β、骨形态发生蛋白、血管内皮生长因子、胰岛素样生长因子"检索CNKI、维普、万方数据库;英文以"BGF、FGF、PDGF、TGF-β、BMP、VEGF、IGF"为检索词检索PubMed数据库,纳入骨生长因子调控骨折愈合机制及其应用研究文章,排除重复及陈旧文献,共纳入文献58篇。结果与结论:各类骨生长因子来源广泛,特点不一,都有各自的作用机制,通过旁分泌、自分泌等多种方式形成局部及系统的协同作用,与靶细胞受体相结合,活化细胞内信号通路,增强细胞功能从而影响细胞迁移、增殖、合成、分化甚至细胞凋亡,有效促进骨愈合、治疗骨缺损。但是骨生长因子具有半衰期短、蛋白易失活等缺陷,通过优化载体设计、递送方式和研发新型生物医学材料能够有效改善骨生长因子的这些缺点,更好地用于骨再生修复。
BACKGROUND: Biocomposite vector inducing the expression of bone growth factors in the fracture parts can effectively shorten the fracture healing time.OBJECTIVE: To review the related literatures and to summarize the mechanism and application progress of bone growth factors regulating fracture healing.METHODS: CNKI, VIP, WanF ang and PubMed databases were retrieved with the keywords of "BGF, FGF, PDGF, TGF-β, BMP, VEGF, IGF"in English and Chinese, respectively. The articles concerning mechanism and application of bone growth factors regulating fracture healing were included, the repetitive studies were excluded, and finally 58 eligible articles were enrolled.RESULTS AND CONCLUSION: Different kinds of bone growth factors are originated from different tissues, and have their own characteristics and action mechanisms. They produce local and systematic synergistic effect by paracrine and autocrine, and bind to the receptors in target cells, further activating the signaling pathways, promoting cell functions, thus affecting cell migration, proliferation,production, differentiation even apoptosis. Therefore, bone growth factors can effectively promote bone healing and treat bone defects. But bone growth factors exhibit shortcomings such as short half-life period and protein inactivation. Optimizing the design and delivery method as well as developing novel biomaterials to effectively overcome all above problems can contribute to bone regeneration and repair.
BACKGROUND: Biocomposite vector inducing the expression of bone growth factors in the fracture parts can effectively shorten the fracture healing time.OBJECTIVE: To review the related literatures and to summarize the mechanism and application progress of bone growth factors regulating fracture healing.METHODS: CNKI, VIP, WanF ang and PubMed databases were retrieved with the keywords of "BGF, FGF, PDGF, TGF-β, BMP, VEGF, IGF"in English and Chinese, respectively. The articles concerning mechanism and application of bone growth factors regulating fracture healing were included, the repetitive studies were excluded, and finally 58 eligible articles were enrolled.RESULTS AND CONCLUSION: Different kinds of bone growth factors are originated from different tissues, and have their own characteristics and action mechanisms. They produce local and systematic synergistic effect by paracrine and autocrine, and bind to the receptors in target cells, further activating the signaling pathways, promoting cell functions, thus affecting cell migration, proliferation,production, differentiation even apoptosis. Therefore, bone growth factors can effectively promote bone healing and treat bone defects. But bone growth factors exhibit shortcomings such as short half-life period and protein inactivation. Optimizing the design and delivery method as well as developing novel biomaterials to effectively overcome all above problems can contribute to bone regeneration and repair.
引文
[1]Zhan D,Xiang W,Guo F,et al.Basic fibroblast growth factor increases IFT88 expression in chondrocytes.Mol Med Rep.2017;16(5):6590-6599.
[2]Yu P,Wilhelm K,Dubrac A,et al.FGF-dependent metabolic control of vascular development.Nature.2017;545(7653):224.
[3]Yamada S,Nagai N,Saijo S,et al.Controlled basic fibroblast growth factor release device made of poly(ethyleneglycol)dimethacrylates for creating a subcutaneous neovascular bed for cell transplantation.J Biomed Mater Res A.2017;105(11):3017-3024.
[4]Patwa JJ,Krishnan A.Buerger's Disease(Thromboangiitis Obliterans)-Management by Ilizarov's Technique of Horizontal Distraction.A Retrospective Study of 60 Cases.Indian J Surg.2011;73(1):40-47.
[5]花奇凯,秦泗河,赵良军,等.Ilizarov技术胫骨横向骨搬移术治疗糖尿病足[J].中国矫形外科杂志,2017,25(4):303-307.
[6]Caroti CM,Ahn H,Salazar HF,et al.A Novel Technique for Accelerated Culture of Murine Mesenchymal Stem Cells that Allows for Sustained Multipotency.Sci Rep.2017;7(1):13334.
[7]Kalomoiris S,Cicchetto AC,Lakatos K,et al.Fibroblast Growth Factor 2 Regulates High Mobility Group A2Expression in Human Bone Marrow‐Derived Mesenchymal Stem Cells.J Cell Biochem.2016;117(9):2128-372137.
[8]Nakajima F,Nakajima A,Ogasawara A,et al.Effects of a Single Percutaneous Injection of Basic Fibroblast Growth Factor on the Healing of a Closed Femoral Shaft Fracture in the Rat.Calcif Tissue Int.2007;81(2):132-138.
[9]Song R,Wang D,Zeng R,et al.Synergistic effects of fibroblast growth factor-2 and bone morphogenetic protein-2 on bone induction.Mol Med Rep.2017;16(4):4483-4492.
[10]Zhang Y,Ma Y,Wu C,et al.Platelet-derived growth factor BBgene-released scaffolds:biosynthesis and characterization.JTissue Eng Regen Med.2016;10(10):E372-E381.
[11]Li DQ,Wan QL,Pathak JL,et al.Platelet-derived growth factor BB enhances osteoclast formation and osteoclast precursor cell chemotaxis.J Bone Miner Metab.2017;35(4):355-365.
[12]Onwuka E,Best C,Sawyer A,et al.The role of myeloid cell-derived PDGF-B in neotissue formation in a tissue-engineered vascular graft.Regen Med.2017;12(3):249-261
[13]Li F,Yu F,Xin X,et al.Evaluation of Recombinant Human FGF-2 and PDGF-BB in Periodontal Regeneration:ASystematic Review and Meta-Analysis.Scientific Reports.2017;7(1):65.
[14]Davies OG,Grover LM,Lewis MP,et al.PDGF is a potent initiator of bone formation in a tissue engineered model of pathological ossification.J Tissue Eng Regen Med.2018;12(1):e355-e367.
[15]Wrana JL,Attisano L,Wieser R,et al.Mechanism of activation of the TGF-βreceptor.Nature.1994;370(6488):341-347.
[16]Garg P,Mazur MM,Buck AC,et al.Prospective Review of Mesenchymal Stem Cells Differentiation into Osteoblasts.Orthopaedic Surgery.2017;9(1):13-19.
[17]Takeyama K,Chatani M,Inohaya K,et al.TGF-β2 signaling is essential for osteoblast migration and differentiation during fracture healing in medaka fish.Bone.2016;86:68-78.
[18]Padua D,MassaguéJ.Roles of TGFbeta in metastasis.Cell Res.2009;19(1):89-102.
[19]Wang X,Liu Y,Chen X,et al.Impact of Mi R-21 on the expression of FasL in the presence of TGF-β1.Aesthet Surg J.2013;33(8):1186-1198.
[20]Wen X,Li X,Tang Y,et al.Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis.J Biol Chem.2016;291(48):24912-24921.
[21]Wang B,Jin H,Zhu M,et al.Chondrocyteβ-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model.Arthritis Rheumatol.2014;66(1):107-120.
[22]Qin J,Wu SP,Creighton CJ,et al.COUP-TFII inhibits TGF-βinduced growth barrier to promote prostate tumorigenesis.Nature.2013;493(7431):236-240.
[23]Bjerke GA,Yang CS,Frierson HF,et al.Activation of Akt signaling in prostate induces a TGF-βmediated restraint on cancer progression and metastasis.Oncogene.2014;33(28):3660.
[24]Johnson MD.Transforming growth factorβfamily in the pathogenesis of meningiomas.World Neurosurg.2017;104:113-119.
[25]Sun KK,Barron L,Hinck CS,et al.An engineered transforming growth factorβ(TGF-β)monomer that functions as a dominant negative to block TGF-βsignaling.J Biological Chemistry.2017;292(17):7173-7188.
[26]周航宇,夏德林,甘生远,等.骨形态发生蛋白2和血管内皮生长因子165双基因转染骨髓基质干细胞的异位诱导成骨能力[J].中国组织工程研究,2017,21(9):1334-1339.
[27]Bolander J,Ji W,Geris L,et al.The combined mechanism of bone morphogenetic protein-and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells.Eur Cell Mater.2016;31:11-25.
[28]Conway JD,Shabtai L,Bauernschub A,et al.BMP-7 versus BMP-2 for the treatment of long bone nonunion.Orthopedics.2014;37(12):1049-57.
[29]Hegarty SV,Sullivan AM,O'Keeffe GW.Endocytosis contributes to BMP2-induced Smad signalling and neuronal growth.Neurosci Lett.2017;643:32-37.
[30]Su YH,Cai HB,Ye ZY,et al.BMP-7 improved proliferation and hematopoietic reconstitution potential of ex vivo expanded cord blood-derived CD34+,cel s.Human Cel.2015;28(1):14-21.
[31]Lei H,Wang J,Lu P,et al.BMP10 inhibited the growth and migration of gastric cancer cells.Tumor Biology.2016;37(3):3025-3031.
[32]Zhang N,Ye L,Wu L,et al.Expression of bone morphogenetic protein-10(BMP10)in human urothelial cancer of the bladder and its effects on the aggressiveness of bladder cancer cells in vitro.Anticancer Res.2013;33(5):1917-1925.
[33]Kallioniemi A.Bone morphogenetic protein 4-a fascinating regulator of cancer cell behavior.Cancer Genet.2012;205(6):267.
[34]Elias E,Nasser Z,Winegan L,et al.Bone Morphogenetic Proteins Usage in Anterior Lumbar Inter-Body Fusion:What Else Can Go Wrong?World Neurosurg.2018;111:55-59.
[35]Faundez A,Tournier C,Garcia M,et al.Bone morphogenetic protein use in spine surgery-complications and outcomes:a systematic review.Int Orthop.2016;40(6):1309-1319.
[36]Subbiah R,Hwang M P,Van S Y,et al.Osteogenic/Angiogenic Dual Growth Factor Delivery Microcapsules for Regeneration of Vascularized Bone Tissue.Adv Healthc Mater.2015;4(13):1982-1992.
[37]Kargozar S,Hashemian SJ,Soleimani M,et al.Acceleration of bone regeneration in bioactive glass/gelatin composite scaffolds seeded with bone marrow-derived mesenchymal stem cells over-expressing bone morphogenetic protein-7.Mater Sci Eng C Mater Biol Appl.2017;1(75):688-698.
[38]Ferrara N,Gerber HP,Lecouter J.The biology of VEGF and its receptors.Nat Med.2003;9(6):669-676.Review.
[39]Liu Y,Olsen BR.Distinct VEGF functions during bone development and homeostasis.Arch Immunol Ther Exp(Warsz).2014;62(5):363-368.
[40]Liu Y,Berendsen AD,Jia S,et al.Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation.J Clin Invest.2012;122(9):3101-3113.
[41]Yang YQ,Tan YY,Wong R,et al.The role of vascular endothelial growth factor in ossification.2012;4(2):64-68.Review.
[42]Bayer EA,Fedorchak MV,Little SR.The Influence of Platelet-Derived Growth Factor and Bone Morphogenetic Protein Presentation on Tubule Organization by Human Umbilical Vascular Endothelial Cells and Human Mesenchymal Stem Cells in Coculture.Tissue Eng Part A.2016;22(21-22):1296-1304.
[43]Street J,Bao M,Deguzman L,et al.Vascular Endothelial Growth Factor Stimulates Bone Repair by Promoting Angiogenesis and Bone Turnover.Proc Natl Acad Sci U S A.2002;99(15):9656-9661.
[44]Motokawa M,Tsuka N,Kaku M,et al.Age-related production of osteoclasts and the changes of serum levels of vascular endothelial growth factor(VEGF)and receptor activator for nuclear factor(NF)-κB ligand(RANKL)in osteopetrotic(op/op)mice.Arch Oral Biol.2012;57(4):352-356.
[45]Huang H,Ma L,Kyrkanides S.Effects of vascular endothelial growth factor on osteoblasts and osteoclasts.Am J Orthod Dentofacial Orthop.2016;149(3):366-373.
[46]Li CJ,Madhu V,Balian G,et al.Cross-Talk Between VEGF and BMP-6 Pathways Accelerates Osteogenic Differentiation of Human Adipose-Derived Stem Cells.J Cell Physiol.2015;230(11):2671-2682.
[47]Zhang Y,Madhu V,Dighe AS,et al.Osteogenic response of human adipose-derived stem cells to BMP-6,VEGF,and combined VEGF plus BMP-6 in vitro.Growth Factors.2012;30(5):333-343.
[48]Chen L,He Z,Chen B,et al.Loading of VEGF to the heparin cross-linked demineralized bone matrix improves vascularization of the scaffold.J Mater Sci Mater Med.2010;21(1):309-317.
[49]Ogilvie CM,Lu C,Marcucio R,et al.Vascular endothelial growth factor improves bone repair in a murine nonunion model.Iowa Orthop J.2012;32:90-94.
[50]Zhu S,Segura T.Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis.Ann Biomed Eng.2016;44(6):1983-1992.
[51]Su YW,Zhou XF,Foster BK,et al.Roles of neurotrophins in skeletal tissue formation and healing.J Cell Physiol.2018;233(3):2133-2145.
[52]Zhang N,Chen J,Ferraro G,et al.Anti-VEGF treatment improves neurological function in tumors of the nervous system.Exp Neurol.2018;299(Pt B):326-333.
[53]Yang ZQ,Zhang HL,Duan CC,et al.IGF1 regulates RUNX1expression via IRS1/2:implications for antler chondrocyte differentiation.Cell Cycle.2017;16(6):522-532.
[54]Zhang Z,Li L,Yang W,et al.The effects of different doses of IGF-1 on cartilage and subchondral bone during the repair of full-thickness articular cartilage defects in rabbits.Osteoarthritis Cartilage.2017;25(2):309-320.
[55]Sheng MH,Zhou XD,Bonewald LF,et al.Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice.Bone.2013;52(1):133-144.
[56]Oikonomopoulos N,Fincher M,Abraham D,et al.IGF-1 has no effect on the proliferation and differentiation of ischaemic myoblasts.British Journal of Surgery.2013:52-53.
[57]Fujioka-Kobayashi M,Schaller B,Zhang Y,et al.Recombinant human bone morphogenetic protein(rhBMP)9 induces osteoblast differentiation when combined with demineralized freeze-dried bone allografts(DFDBAs)or biphasic calcium phosphate(BCP).Clin Oral Investig.2017;21(5):1883-1893.
[58]Inoue G,Uchida K,Matsushita O,et al.Effect of Freeze-Dried Allograft Bone with Human Basic Fibroblast Growth Factor Containing a Collagen-Binding Domain from Clostridium Histolyticum Collagenase on Bone Formation after Lumbar Posterolateral Fusion Surgery in Rats.Spine.2017;42(17):E995-E1001.
[2]Yu P,Wilhelm K,Dubrac A,et al.FGF-dependent metabolic control of vascular development.Nature.2017;545(7653):224.
[3]Yamada S,Nagai N,Saijo S,et al.Controlled basic fibroblast growth factor release device made of poly(ethyleneglycol)dimethacrylates for creating a subcutaneous neovascular bed for cell transplantation.J Biomed Mater Res A.2017;105(11):3017-3024.
[4]Patwa JJ,Krishnan A.Buerger's Disease(Thromboangiitis Obliterans)-Management by Ilizarov's Technique of Horizontal Distraction.A Retrospective Study of 60 Cases.Indian J Surg.2011;73(1):40-47.
[5]花奇凯,秦泗河,赵良军,等.Ilizarov技术胫骨横向骨搬移术治疗糖尿病足[J].中国矫形外科杂志,2017,25(4):303-307.
[6]Caroti CM,Ahn H,Salazar HF,et al.A Novel Technique for Accelerated Culture of Murine Mesenchymal Stem Cells that Allows for Sustained Multipotency.Sci Rep.2017;7(1):13334.
[7]Kalomoiris S,Cicchetto AC,Lakatos K,et al.Fibroblast Growth Factor 2 Regulates High Mobility Group A2Expression in Human Bone Marrow‐Derived Mesenchymal Stem Cells.J Cell Biochem.2016;117(9):2128-372137.
[8]Nakajima F,Nakajima A,Ogasawara A,et al.Effects of a Single Percutaneous Injection of Basic Fibroblast Growth Factor on the Healing of a Closed Femoral Shaft Fracture in the Rat.Calcif Tissue Int.2007;81(2):132-138.
[9]Song R,Wang D,Zeng R,et al.Synergistic effects of fibroblast growth factor-2 and bone morphogenetic protein-2 on bone induction.Mol Med Rep.2017;16(4):4483-4492.
[10]Zhang Y,Ma Y,Wu C,et al.Platelet-derived growth factor BBgene-released scaffolds:biosynthesis and characterization.JTissue Eng Regen Med.2016;10(10):E372-E381.
[11]Li DQ,Wan QL,Pathak JL,et al.Platelet-derived growth factor BB enhances osteoclast formation and osteoclast precursor cell chemotaxis.J Bone Miner Metab.2017;35(4):355-365.
[12]Onwuka E,Best C,Sawyer A,et al.The role of myeloid cell-derived PDGF-B in neotissue formation in a tissue-engineered vascular graft.Regen Med.2017;12(3):249-261
[13]Li F,Yu F,Xin X,et al.Evaluation of Recombinant Human FGF-2 and PDGF-BB in Periodontal Regeneration:ASystematic Review and Meta-Analysis.Scientific Reports.2017;7(1):65.
[14]Davies OG,Grover LM,Lewis MP,et al.PDGF is a potent initiator of bone formation in a tissue engineered model of pathological ossification.J Tissue Eng Regen Med.2018;12(1):e355-e367.
[15]Wrana JL,Attisano L,Wieser R,et al.Mechanism of activation of the TGF-βreceptor.Nature.1994;370(6488):341-347.
[16]Garg P,Mazur MM,Buck AC,et al.Prospective Review of Mesenchymal Stem Cells Differentiation into Osteoblasts.Orthopaedic Surgery.2017;9(1):13-19.
[17]Takeyama K,Chatani M,Inohaya K,et al.TGF-β2 signaling is essential for osteoblast migration and differentiation during fracture healing in medaka fish.Bone.2016;86:68-78.
[18]Padua D,MassaguéJ.Roles of TGFbeta in metastasis.Cell Res.2009;19(1):89-102.
[19]Wang X,Liu Y,Chen X,et al.Impact of Mi R-21 on the expression of FasL in the presence of TGF-β1.Aesthet Surg J.2013;33(8):1186-1198.
[20]Wen X,Li X,Tang Y,et al.Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis.J Biol Chem.2016;291(48):24912-24921.
[21]Wang B,Jin H,Zhu M,et al.Chondrocyteβ-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model.Arthritis Rheumatol.2014;66(1):107-120.
[22]Qin J,Wu SP,Creighton CJ,et al.COUP-TFII inhibits TGF-βinduced growth barrier to promote prostate tumorigenesis.Nature.2013;493(7431):236-240.
[23]Bjerke GA,Yang CS,Frierson HF,et al.Activation of Akt signaling in prostate induces a TGF-βmediated restraint on cancer progression and metastasis.Oncogene.2014;33(28):3660.
[24]Johnson MD.Transforming growth factorβfamily in the pathogenesis of meningiomas.World Neurosurg.2017;104:113-119.
[25]Sun KK,Barron L,Hinck CS,et al.An engineered transforming growth factorβ(TGF-β)monomer that functions as a dominant negative to block TGF-βsignaling.J Biological Chemistry.2017;292(17):7173-7188.
[26]周航宇,夏德林,甘生远,等.骨形态发生蛋白2和血管内皮生长因子165双基因转染骨髓基质干细胞的异位诱导成骨能力[J].中国组织工程研究,2017,21(9):1334-1339.
[27]Bolander J,Ji W,Geris L,et al.The combined mechanism of bone morphogenetic protein-and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells.Eur Cell Mater.2016;31:11-25.
[28]Conway JD,Shabtai L,Bauernschub A,et al.BMP-7 versus BMP-2 for the treatment of long bone nonunion.Orthopedics.2014;37(12):1049-57.
[29]Hegarty SV,Sullivan AM,O'Keeffe GW.Endocytosis contributes to BMP2-induced Smad signalling and neuronal growth.Neurosci Lett.2017;643:32-37.
[30]Su YH,Cai HB,Ye ZY,et al.BMP-7 improved proliferation and hematopoietic reconstitution potential of ex vivo expanded cord blood-derived CD34+,cel s.Human Cel.2015;28(1):14-21.
[31]Lei H,Wang J,Lu P,et al.BMP10 inhibited the growth and migration of gastric cancer cells.Tumor Biology.2016;37(3):3025-3031.
[32]Zhang N,Ye L,Wu L,et al.Expression of bone morphogenetic protein-10(BMP10)in human urothelial cancer of the bladder and its effects on the aggressiveness of bladder cancer cells in vitro.Anticancer Res.2013;33(5):1917-1925.
[33]Kallioniemi A.Bone morphogenetic protein 4-a fascinating regulator of cancer cell behavior.Cancer Genet.2012;205(6):267.
[34]Elias E,Nasser Z,Winegan L,et al.Bone Morphogenetic Proteins Usage in Anterior Lumbar Inter-Body Fusion:What Else Can Go Wrong?World Neurosurg.2018;111:55-59.
[35]Faundez A,Tournier C,Garcia M,et al.Bone morphogenetic protein use in spine surgery-complications and outcomes:a systematic review.Int Orthop.2016;40(6):1309-1319.
[36]Subbiah R,Hwang M P,Van S Y,et al.Osteogenic/Angiogenic Dual Growth Factor Delivery Microcapsules for Regeneration of Vascularized Bone Tissue.Adv Healthc Mater.2015;4(13):1982-1992.
[37]Kargozar S,Hashemian SJ,Soleimani M,et al.Acceleration of bone regeneration in bioactive glass/gelatin composite scaffolds seeded with bone marrow-derived mesenchymal stem cells over-expressing bone morphogenetic protein-7.Mater Sci Eng C Mater Biol Appl.2017;1(75):688-698.
[38]Ferrara N,Gerber HP,Lecouter J.The biology of VEGF and its receptors.Nat Med.2003;9(6):669-676.Review.
[39]Liu Y,Olsen BR.Distinct VEGF functions during bone development and homeostasis.Arch Immunol Ther Exp(Warsz).2014;62(5):363-368.
[40]Liu Y,Berendsen AD,Jia S,et al.Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation.J Clin Invest.2012;122(9):3101-3113.
[41]Yang YQ,Tan YY,Wong R,et al.The role of vascular endothelial growth factor in ossification.2012;4(2):64-68.Review.
[42]Bayer EA,Fedorchak MV,Little SR.The Influence of Platelet-Derived Growth Factor and Bone Morphogenetic Protein Presentation on Tubule Organization by Human Umbilical Vascular Endothelial Cells and Human Mesenchymal Stem Cells in Coculture.Tissue Eng Part A.2016;22(21-22):1296-1304.
[43]Street J,Bao M,Deguzman L,et al.Vascular Endothelial Growth Factor Stimulates Bone Repair by Promoting Angiogenesis and Bone Turnover.Proc Natl Acad Sci U S A.2002;99(15):9656-9661.
[44]Motokawa M,Tsuka N,Kaku M,et al.Age-related production of osteoclasts and the changes of serum levels of vascular endothelial growth factor(VEGF)and receptor activator for nuclear factor(NF)-κB ligand(RANKL)in osteopetrotic(op/op)mice.Arch Oral Biol.2012;57(4):352-356.
[45]Huang H,Ma L,Kyrkanides S.Effects of vascular endothelial growth factor on osteoblasts and osteoclasts.Am J Orthod Dentofacial Orthop.2016;149(3):366-373.
[46]Li CJ,Madhu V,Balian G,et al.Cross-Talk Between VEGF and BMP-6 Pathways Accelerates Osteogenic Differentiation of Human Adipose-Derived Stem Cells.J Cell Physiol.2015;230(11):2671-2682.
[47]Zhang Y,Madhu V,Dighe AS,et al.Osteogenic response of human adipose-derived stem cells to BMP-6,VEGF,and combined VEGF plus BMP-6 in vitro.Growth Factors.2012;30(5):333-343.
[48]Chen L,He Z,Chen B,et al.Loading of VEGF to the heparin cross-linked demineralized bone matrix improves vascularization of the scaffold.J Mater Sci Mater Med.2010;21(1):309-317.
[49]Ogilvie CM,Lu C,Marcucio R,et al.Vascular endothelial growth factor improves bone repair in a murine nonunion model.Iowa Orthop J.2012;32:90-94.
[50]Zhu S,Segura T.Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis.Ann Biomed Eng.2016;44(6):1983-1992.
[51]Su YW,Zhou XF,Foster BK,et al.Roles of neurotrophins in skeletal tissue formation and healing.J Cell Physiol.2018;233(3):2133-2145.
[52]Zhang N,Chen J,Ferraro G,et al.Anti-VEGF treatment improves neurological function in tumors of the nervous system.Exp Neurol.2018;299(Pt B):326-333.
[53]Yang ZQ,Zhang HL,Duan CC,et al.IGF1 regulates RUNX1expression via IRS1/2:implications for antler chondrocyte differentiation.Cell Cycle.2017;16(6):522-532.
[54]Zhang Z,Li L,Yang W,et al.The effects of different doses of IGF-1 on cartilage and subchondral bone during the repair of full-thickness articular cartilage defects in rabbits.Osteoarthritis Cartilage.2017;25(2):309-320.
[55]Sheng MH,Zhou XD,Bonewald LF,et al.Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice.Bone.2013;52(1):133-144.
[56]Oikonomopoulos N,Fincher M,Abraham D,et al.IGF-1 has no effect on the proliferation and differentiation of ischaemic myoblasts.British Journal of Surgery.2013:52-53.
[57]Fujioka-Kobayashi M,Schaller B,Zhang Y,et al.Recombinant human bone morphogenetic protein(rhBMP)9 induces osteoblast differentiation when combined with demineralized freeze-dried bone allografts(DFDBAs)or biphasic calcium phosphate(BCP).Clin Oral Investig.2017;21(5):1883-1893.
[58]Inoue G,Uchida K,Matsushita O,et al.Effect of Freeze-Dried Allograft Bone with Human Basic Fibroblast Growth Factor Containing a Collagen-Binding Domain from Clostridium Histolyticum Collagenase on Bone Formation after Lumbar Posterolateral Fusion Surgery in Rats.Spine.2017;42(17):E995-E1001.