Wnt/β-catenin与BMP-2/Smads信号通路及其相互作用对骨质疏松疾病的影响
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摘要
[目的]对Wnt/β-连环蛋白(β-catenin)和骨形态发生蛋白(bone morphogenetic protein,BMP-2)/Smads信号通路在骨代谢中的作用及其在骨质疏松症(osteoporosis,OP)预防和治疗中的作用进行综述,以期为OP相关疾病的预防和治疗提供新思路。[方法]通过中国知网、万方、Pubmed等数据库检索近年来国内外关于Wnt/β-catenin与BMP-2/Smads信号通路与OP疾病关系的实验研究文献,总结Wnt/β-catenin与BMP-2/Smads信号通路与OP疾病关系的研究概况。[结果]①Wnt/β-catenin信号传导对于骨骼谱系分化至关重要,可防止成骨细胞转分化为软骨细胞。其中的负调控信号分子可能是治疗骨质疏松症的药物靶点,并成为药物治疗骨质疏松症的手段之一。②BMP-2/Smads信号通路中的信号分子可用于骨质疏松靶标的治疗,但其应用时间、浓度也应再继续深入研究,以期达到更好的治疗骨质疏松的效果。③Wnt/β-catenin和BMP-2/Smads信号通路在许多生物学行为中相互重叠、互补或抑制,提示两种信号途径之间存在着复杂的交联关系。[结论] Wnt/β-catenin和BMP-2/Smads信号通路是调节成骨细胞生长、发育和分化的两个重要信号通路,在成骨细胞分化和骨形成过程中发挥重要作用。Wnt/β-catenin和BMP-2/Smads信号通路在OP的预防、治疗及新药的研制和开发中具有广泛应用前景。
[Objective]To summarize the role of Wnt/β-catenin and BMP-2/Smads signaling pathways in bone metabolism and their role in the prevention and treatment of osteoporosis(OP), with a view to provide new ideas for the prevention and treatment of OP-related diseases.[Methods]The experimental literature on the relationship between Wnt-catenin and BMP-2 smads signal pathway and OP disease was retrieved from Wanfang Pubmed and other databases of CNKI in recent years, and the research overview on the relationship between Wnt/β-catenin and BMP-2/Smads signal pathway and OP disease was summarized.[Results]①Wnt/β-catenin signaling is essential for skeletal lineage differentiation and prevents osteoblasts from transdifferentiating into chondrocytes.The negative regulatory signaling molecule may be a drug target for the treatment of osteoporosis and become one of the means of drug treatment for osteoporosis. ② Signal molecules in the BMP-2/Smads signaling pathway can be used for the treatment of osteoporosis targets, but their application time and concentration should be further studied in order to achieve better treatment of osteoporosis. ③Wnt/β-catenin and BMP-2/Smads signaling pathways overlap, complement or inhibit in many biological behaviors, suggesting a complex cross-linking relationship between the two signaling pathways.[Conclusion] Wnt/β-catenin and BMP-2/Smads are two important signaling pathways that regulate cell growth, development and differentiation,and play important roles in osteoblast differentiation and bone formation. Wnt/β-catenin and BMP-2/Smads signaling pathways have broad application prospects in the prevention, treatment and development of new drugs.
[Objective]To summarize the role of Wnt/β-catenin and BMP-2/Smads signaling pathways in bone metabolism and their role in the prevention and treatment of osteoporosis(OP), with a view to provide new ideas for the prevention and treatment of OP-related diseases.[Methods]The experimental literature on the relationship between Wnt-catenin and BMP-2 smads signal pathway and OP disease was retrieved from Wanfang Pubmed and other databases of CNKI in recent years, and the research overview on the relationship between Wnt/β-catenin and BMP-2/Smads signal pathway and OP disease was summarized.[Results]①Wnt/β-catenin signaling is essential for skeletal lineage differentiation and prevents osteoblasts from transdifferentiating into chondrocytes.The negative regulatory signaling molecule may be a drug target for the treatment of osteoporosis and become one of the means of drug treatment for osteoporosis. ② Signal molecules in the BMP-2/Smads signaling pathway can be used for the treatment of osteoporosis targets, but their application time and concentration should be further studied in order to achieve better treatment of osteoporosis. ③Wnt/β-catenin and BMP-2/Smads signaling pathways overlap, complement or inhibit in many biological behaviors, suggesting a complex cross-linking relationship between the two signaling pathways.[Conclusion] Wnt/β-catenin and BMP-2/Smads are two important signaling pathways that regulate cell growth, development and differentiation,and play important roles in osteoblast differentiation and bone formation. Wnt/β-catenin and BMP-2/Smads signaling pathways have broad application prospects in the prevention, treatment and development of new drugs.
引文
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[3]姚新苗,冷涛,张云鹏.益骨口服液含药血清对成骨细胞增殖、分化及矿化功能的影响[J].中国中医骨伤科杂志,2010,18(1):6-8.
[4]Baron R,Kneissel M.WNT signaling in bone homeostasis and disease:from human mutations to treatments[J].Nature Medicine,2013,19(2):179-192.
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[6]仝晓阳,张玲莉,郭健民,等.运动对骨代谢信号通路影响的研究进展[J].中国康复理论与实践,2016,22(12):1425-1429.
[7]Joiner D M,Ke J,Zhong Z,et al.LRP5 and LRP6 in development and disease[J].Trends in Endocrinology&Metabolism,2012,24(1):31-39.
[8]Niehrs C,Shen J.Regulation of Lrp6 phosphorylation[J].Cellular and Molecular Life Sciences,2010,67(15):2551-2562.
[9]Kestler H A,Kuhl M.From individual Wnt pathways towards a Wnt signalling network[J].Philosophical Transactions of the Royal Society B:Biological Sciences,2008,363(1495):1333-1347.
[10]Pinzone J J,Hall B M,Thudi N K,et al.The role of Dickkopf-1 in bone development,homeostasis,and disease[J].Blood,2009,113(3):517-525.
[11]Monroe D G,Mcgee-Lawrence M E,Oursler M J,et al.Update on Wnt signaling in bone cell biology and bone disease[J].Gene,2012,492(1):1-18.
[12]Vinyoles M,Del Valle-Pérez B,Curto J,et al.Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6[J].Molecular Cell,2014,53(3):444-457.
[13]Wan Y,Wei W,Zeve D,et al.Biphasic and dosage-dependent regulation of osteoclastogenesis by beta-catenin[J].Bone,2011,48:S160.
[14]Bennett C N,Ross S E,Longo K A,et al.Regulation of Wnt signaling during adipogenesis[J].Journal of Biological Chemistry,2002,277(34):30998-31004.
[15]Kato M,Patel M S,Levasseur R,et al.Cbfa1-independent decrease in osteoblast proliferation,osteopenia,and persistent embryonic eye vascularization in mice deficient in Lrp5,a Wnt coreceptor[J].J Cell Biol,2002,157(2):303-314.
[16]Hill T P,Sp?ter D,Taketo M M,et al.Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into Chondrocytes[J].Developmental Cell,2005,8(5):727-738.
[17]Erming Tian B S F Z.The role of the Wnt-signaling antagonist Dkk1 in the development of osteolytic lesions in multiple myeloma[J].The new england journal of medicine,2010,21(4):372.
[18]Wang F,Ko J,Lin C,et al.Knocking down dickkopf-1alleviates estrogen deficiency induction of bone loss:Ahistomorphological study in ovariectomized rats[J].Bone,2007,40(2):485-492.
[19]Clarke D C,Liu X.Decoding the quantitative nature of TGF-β/Smads signaling[J].Trends in Cell Biology,2008,18(9):430-442.
[20]Dijke P T,Hill C S.New insights into TGF-β-Smads signalling[J].Trends in Biochemical Sciences,2004,29(5):265-273.
[21]Gautschi O P,Frey S P,Zellweger R.Bone morphogenetic proteins in clinical applications[J].ANZ Journal of Surgery,2007,77(8):626-631.
[22]Ripamonti U.Soluble osteogenic molecular signals and the induction of bone formation[J].Biomaterials,2006,27(6):807-822.
[23]Chen H B.Identification of phosphatases for Smads in the BMP/DPP pathway[J].Genes&Development,2006,20(6):648-653.
[24]Rosen V.BMP2 signaling in bone development and repair[J].Cytokine&Growth Factor Reviews,2009,20(5-6):475-480.
[25]Groppe J,Greenwald J,Wiater E,et al.Structural basis of BMP signalling inhibition by the cystine knot protein Noggin[J].Nature,2002,420(6916):636-642.
[26]Groppe J,Greenwald J,Wiater E,et al.Structural basis of BMP signaling inhibition by the cystine knot protein Noggin[J].Nature,2002,420(6916):636-642.
[27]Zhang H,Bradley A.Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development[J].Development,1996,122(10):2977-2986.
[28]Bandyopadhyay A,Tsuji K,Cox K,et al.Genetic analysis of the roles of BMP2,BMP4,and BMP7 in limb patterning and skeletogenesis[J].PLoS Genet,2006,2(12):e216.
[29]Bais M V,Wigner N,Young M,et al.BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells[J].Bone,2009,45(2):254-266.
[30]Gupta M C,Khan S N.Application of bone morphogenetic proteins in spinal fusion[J].Cytokine&Growth Factor Reviews,2005,16(3):347-355.
[31]Di C,Ming Z,Gregory R M.Bone morphogenetic proteins.[J].Growth Factors(Chur,Switzerland),2004,22(4)233-241.
[32]Tang J,Song M,Wang Y,et al.Noggin and BMP4 comodulate adult hippocampal neurogenesis in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease[J].Biochemical and Biophysical Research Communications,2009,385(3):341-345.
[33]Thomeer H G,Admiraal R J,Hoefsloot L,et al.Proximal symphalangism,hyperopia,conductive hearing impairment,and the NOG gene:2 new mutations[J].Otol Neurotol,2011,32(4):632-638.
[34]Woo E J.Recombinant human bone morphogenetic protein-2:Adverse events reported to the Manufacturer and User Facility Device Experience Database[J].The Spine Journal,2012,12(10):894-899.
[35]Woo E J.Adverse events after recombinant human BMP2in nonspinal orthopaedic procedures[J].Clin Orthop Relat Res,2013,471(5):1707-1711.
[36]Dmitriev A E,Lehman R A,Symes A J.Bone morphogenetic protein-2 and spinal arthrodesis:The basic science perspective on protein interaction with the nervous system[J].Spine Journal,2011,11(6):500-505.
[37]Pradhan B B,Bae H W,Dawson E G,et al.Graft resorption with the use of bone morphogenetic protein:lessons from anterior lumbar interbody fusion using femoral ring allografts and recombinant human bone morphogenetic protein-2[J].Spine(Phila Pa 1976),2006,31(10):E277-E284.
[38]Lee K B,Taghavi C E,Murray S S,et al.BMP induced inflammation:A comparison of rhBMP-7 and rhBMP-2[J].J Orthop Res,2012,30(12):1985-1994.
[39]Smoljanovic T,Bojanic I,Dokuzovic S.Recombinant human bone morphogenetic protein-2-induced radiculitis in elective minimally invasive transforaminal lumbar interbody fusions:A series review[J].Spine,2010,35(8):929.
[40]Shields L B,Raque G H,Glassman S D,et al.Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion[J].Spine(Phila Pa 1976),2006,31(5):542-547.
[41]Rihn J A,Makda J,Hong J,et al.The use of RhBMP-2 in single-level transforaminal lumbar interbody fusion:a clinical and radiographic analysis[J].European Spine Journal,2009,18(11):1629-1636.
[42]Carragee E J,Mitsunaga K A,Hurwitz E L,et al.Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2:A cohort controlled study[J].Spine Journal,2011,11(6):511-516.
[43]Rawadi G,Vayssiere B,Dunn F,et al.BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop[J].J Bone Miner Res,2003,18(10):1842-1853.
[44]Kamiya N,Kobayashi T,Mochida Y,et al.Wnt inhibitors Dkk1 and Sost are downstream targets of BMPsignaling through the type IA receptor(BMPRIA)in osteoblasts[J].Journal of Bone and Mineral Research,2010,25(2):200-210.
[45]Eivers E,Demagny H,Choi R H,et al.Phosphorylation of Mad controls competition between wingless and BMPsignaling[J].Science signaling,2011,4(194):a68.
[46]Tang Y,Liu Z,Zhao L,et al.Smads 7 stabilizesβ-catenin binding to E-cadherin complex and promotes cell-cell adhesion[J].Journal of Biological Chemistry,2008,283(35):23956-23963.
[47]Bain G,Müller T,Wang X,et al.Activatedβ-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction[J].Biochemical and Biophysical Research Communications,2003,301(1):84-91.
[48]Chen Y,Whetstone H C,Youn A,et al.β-Catenin signaling pathway is crucial for bone morphogenetic protein 2to induce new bone formation[J].Journal of Biological Chemistry,2006,282(1):526-533.
[49]Hill T P,Sp ter D,Taketo M M,et al.Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes[J].Developmental Cell,2005,8(5):727-738.
[50]Hill T P.Multiple roles of mesenchymal-catenin during murine limb patterning[J].Development,2006,133(7):1219-1229.
[51]Kamiya N,Kobayashi T,Mochida Y,et al.Wnt inhibitors Dkk1 and SOST are downstream targets of BMPsignaling through the type IA receptor(BMPRIA)in osteoblasts[J].Journal of Bone and Mineral Research,2010,25(2):200-210.
[52]Kim H K W,Oxendine I,Kamiya N.High-concentration of BMP2 reduces cell proliferation and increases apoptosis via Dkk1 and SOST in human primary periosteal cells[J].Bone,2013,54(1):141-150.
[53]Abe E,Yamamoto M,Taguchi Y,et al.Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice:antagonism by noggin[J].J Bone Miner Res,2000,15(4):663-673.
[2]Lin X,Xiong D,Peng Y Q,et al.Epidemiology and management of osteoporosis in the People's Republic of China:current perspectives[J].Clin Interv Aging,2015,10:1017-1033.
[3]姚新苗,冷涛,张云鹏.益骨口服液含药血清对成骨细胞增殖、分化及矿化功能的影响[J].中国中医骨伤科杂志,2010,18(1):6-8.
[4]Baron R,Kneissel M.WNT signaling in bone homeostasis and disease:from human mutations to treatments[J].Nature Medicine,2013,19(2):179-192.
[5]Sieber C,Kopf J,Hiepen C,et al.Recent advances in BMP receptor signaling[J].Cytokine&Growth Factor Reviews,2009,20(5-6):343-355.
[6]仝晓阳,张玲莉,郭健民,等.运动对骨代谢信号通路影响的研究进展[J].中国康复理论与实践,2016,22(12):1425-1429.
[7]Joiner D M,Ke J,Zhong Z,et al.LRP5 and LRP6 in development and disease[J].Trends in Endocrinology&Metabolism,2012,24(1):31-39.
[8]Niehrs C,Shen J.Regulation of Lrp6 phosphorylation[J].Cellular and Molecular Life Sciences,2010,67(15):2551-2562.
[9]Kestler H A,Kuhl M.From individual Wnt pathways towards a Wnt signalling network[J].Philosophical Transactions of the Royal Society B:Biological Sciences,2008,363(1495):1333-1347.
[10]Pinzone J J,Hall B M,Thudi N K,et al.The role of Dickkopf-1 in bone development,homeostasis,and disease[J].Blood,2009,113(3):517-525.
[11]Monroe D G,Mcgee-Lawrence M E,Oursler M J,et al.Update on Wnt signaling in bone cell biology and bone disease[J].Gene,2012,492(1):1-18.
[12]Vinyoles M,Del Valle-Pérez B,Curto J,et al.Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6[J].Molecular Cell,2014,53(3):444-457.
[13]Wan Y,Wei W,Zeve D,et al.Biphasic and dosage-dependent regulation of osteoclastogenesis by beta-catenin[J].Bone,2011,48:S160.
[14]Bennett C N,Ross S E,Longo K A,et al.Regulation of Wnt signaling during adipogenesis[J].Journal of Biological Chemistry,2002,277(34):30998-31004.
[15]Kato M,Patel M S,Levasseur R,et al.Cbfa1-independent decrease in osteoblast proliferation,osteopenia,and persistent embryonic eye vascularization in mice deficient in Lrp5,a Wnt coreceptor[J].J Cell Biol,2002,157(2):303-314.
[16]Hill T P,Sp?ter D,Taketo M M,et al.Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into Chondrocytes[J].Developmental Cell,2005,8(5):727-738.
[17]Erming Tian B S F Z.The role of the Wnt-signaling antagonist Dkk1 in the development of osteolytic lesions in multiple myeloma[J].The new england journal of medicine,2010,21(4):372.
[18]Wang F,Ko J,Lin C,et al.Knocking down dickkopf-1alleviates estrogen deficiency induction of bone loss:Ahistomorphological study in ovariectomized rats[J].Bone,2007,40(2):485-492.
[19]Clarke D C,Liu X.Decoding the quantitative nature of TGF-β/Smads signaling[J].Trends in Cell Biology,2008,18(9):430-442.
[20]Dijke P T,Hill C S.New insights into TGF-β-Smads signalling[J].Trends in Biochemical Sciences,2004,29(5):265-273.
[21]Gautschi O P,Frey S P,Zellweger R.Bone morphogenetic proteins in clinical applications[J].ANZ Journal of Surgery,2007,77(8):626-631.
[22]Ripamonti U.Soluble osteogenic molecular signals and the induction of bone formation[J].Biomaterials,2006,27(6):807-822.
[23]Chen H B.Identification of phosphatases for Smads in the BMP/DPP pathway[J].Genes&Development,2006,20(6):648-653.
[24]Rosen V.BMP2 signaling in bone development and repair[J].Cytokine&Growth Factor Reviews,2009,20(5-6):475-480.
[25]Groppe J,Greenwald J,Wiater E,et al.Structural basis of BMP signalling inhibition by the cystine knot protein Noggin[J].Nature,2002,420(6916):636-642.
[26]Groppe J,Greenwald J,Wiater E,et al.Structural basis of BMP signaling inhibition by the cystine knot protein Noggin[J].Nature,2002,420(6916):636-642.
[27]Zhang H,Bradley A.Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development[J].Development,1996,122(10):2977-2986.
[28]Bandyopadhyay A,Tsuji K,Cox K,et al.Genetic analysis of the roles of BMP2,BMP4,and BMP7 in limb patterning and skeletogenesis[J].PLoS Genet,2006,2(12):e216.
[29]Bais M V,Wigner N,Young M,et al.BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells[J].Bone,2009,45(2):254-266.
[30]Gupta M C,Khan S N.Application of bone morphogenetic proteins in spinal fusion[J].Cytokine&Growth Factor Reviews,2005,16(3):347-355.
[31]Di C,Ming Z,Gregory R M.Bone morphogenetic proteins.[J].Growth Factors(Chur,Switzerland),2004,22(4)233-241.
[32]Tang J,Song M,Wang Y,et al.Noggin and BMP4 comodulate adult hippocampal neurogenesis in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease[J].Biochemical and Biophysical Research Communications,2009,385(3):341-345.
[33]Thomeer H G,Admiraal R J,Hoefsloot L,et al.Proximal symphalangism,hyperopia,conductive hearing impairment,and the NOG gene:2 new mutations[J].Otol Neurotol,2011,32(4):632-638.
[34]Woo E J.Recombinant human bone morphogenetic protein-2:Adverse events reported to the Manufacturer and User Facility Device Experience Database[J].The Spine Journal,2012,12(10):894-899.
[35]Woo E J.Adverse events after recombinant human BMP2in nonspinal orthopaedic procedures[J].Clin Orthop Relat Res,2013,471(5):1707-1711.
[36]Dmitriev A E,Lehman R A,Symes A J.Bone morphogenetic protein-2 and spinal arthrodesis:The basic science perspective on protein interaction with the nervous system[J].Spine Journal,2011,11(6):500-505.
[37]Pradhan B B,Bae H W,Dawson E G,et al.Graft resorption with the use of bone morphogenetic protein:lessons from anterior lumbar interbody fusion using femoral ring allografts and recombinant human bone morphogenetic protein-2[J].Spine(Phila Pa 1976),2006,31(10):E277-E284.
[38]Lee K B,Taghavi C E,Murray S S,et al.BMP induced inflammation:A comparison of rhBMP-7 and rhBMP-2[J].J Orthop Res,2012,30(12):1985-1994.
[39]Smoljanovic T,Bojanic I,Dokuzovic S.Recombinant human bone morphogenetic protein-2-induced radiculitis in elective minimally invasive transforaminal lumbar interbody fusions:A series review[J].Spine,2010,35(8):929.
[40]Shields L B,Raque G H,Glassman S D,et al.Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion[J].Spine(Phila Pa 1976),2006,31(5):542-547.
[41]Rihn J A,Makda J,Hong J,et al.The use of RhBMP-2 in single-level transforaminal lumbar interbody fusion:a clinical and radiographic analysis[J].European Spine Journal,2009,18(11):1629-1636.
[42]Carragee E J,Mitsunaga K A,Hurwitz E L,et al.Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2:A cohort controlled study[J].Spine Journal,2011,11(6):511-516.
[43]Rawadi G,Vayssiere B,Dunn F,et al.BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop[J].J Bone Miner Res,2003,18(10):1842-1853.
[44]Kamiya N,Kobayashi T,Mochida Y,et al.Wnt inhibitors Dkk1 and Sost are downstream targets of BMPsignaling through the type IA receptor(BMPRIA)in osteoblasts[J].Journal of Bone and Mineral Research,2010,25(2):200-210.
[45]Eivers E,Demagny H,Choi R H,et al.Phosphorylation of Mad controls competition between wingless and BMPsignaling[J].Science signaling,2011,4(194):a68.
[46]Tang Y,Liu Z,Zhao L,et al.Smads 7 stabilizesβ-catenin binding to E-cadherin complex and promotes cell-cell adhesion[J].Journal of Biological Chemistry,2008,283(35):23956-23963.
[47]Bain G,Müller T,Wang X,et al.Activatedβ-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction[J].Biochemical and Biophysical Research Communications,2003,301(1):84-91.
[48]Chen Y,Whetstone H C,Youn A,et al.β-Catenin signaling pathway is crucial for bone morphogenetic protein 2to induce new bone formation[J].Journal of Biological Chemistry,2006,282(1):526-533.
[49]Hill T P,Sp ter D,Taketo M M,et al.Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes[J].Developmental Cell,2005,8(5):727-738.
[50]Hill T P.Multiple roles of mesenchymal-catenin during murine limb patterning[J].Development,2006,133(7):1219-1229.
[51]Kamiya N,Kobayashi T,Mochida Y,et al.Wnt inhibitors Dkk1 and SOST are downstream targets of BMPsignaling through the type IA receptor(BMPRIA)in osteoblasts[J].Journal of Bone and Mineral Research,2010,25(2):200-210.
[52]Kim H K W,Oxendine I,Kamiya N.High-concentration of BMP2 reduces cell proliferation and increases apoptosis via Dkk1 and SOST in human primary periosteal cells[J].Bone,2013,54(1):141-150.
[53]Abe E,Yamamoto M,Taguchi Y,et al.Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice:antagonism by noggin[J].J Bone Miner Res,2000,15(4):663-673.