Runx2在成骨细胞和软骨细胞分化中作用的研究进展
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摘要
Runx2是一种转录因子,能诱导在不成熟骨细胞向成熟的成骨细胞分化过程中起重要作用的转录因子Sp7,Sp7和经典Wnt信号转导将骨祖细胞直接分化为成骨细胞,从而抑制软骨细胞分化。同时Runx2通过诱导印度豪猪蛋白(Ihh)增强软骨细胞增殖,高表达的Ihh诱导甲状旁腺激素样激素的生成,抑制Runx2和软骨细胞成熟,形成软骨细胞成熟的负反馈调节。Runx2还是骨关节炎发病机制的基因之一,Runx2在骨关节炎软骨中的软骨细胞中表达明显上调,关节软骨细胞中Runx2的缺失会减缓骨关节炎进展。故该基因对成骨细胞分化和软骨细胞成熟至关重要,并参与骨关节炎的发病机制。
Runx2 is a transcription factor that can induce Sp7,which plays an important role in the differentiation of immature osteoblasts into mature osteoblasts. Sp7 and classical Wnt signal transduction can directly differentiate bone progenitor cells into osteoblasts,thereby inhibiting chondrocyte differentiation. At the same time,Runx2 enhances chondrocyte proliferation by inducing Indian porcupine protein( Ihh),and high expression of Ihh induces production of parathyroid hormone like hormone,inhibits Runx2 and chondrocyte maturation,and forms negative feedback regulation of chondrocyte maturation. Runx2 is also one of the genes responsible for the pathogenesis of osteoarthritis. Runx2 is significantly up-regulated in chondrocytes in osteoarthritis cartilage,and the absence of Runx2 in articular chondrocytes may slow the progression of osteoarthritis,which indicates that it is essential for osteoblast differentiation and chondrocyte maturation,and is involved in osteoarthritis.
Runx2 is a transcription factor that can induce Sp7,which plays an important role in the differentiation of immature osteoblasts into mature osteoblasts. Sp7 and classical Wnt signal transduction can directly differentiate bone progenitor cells into osteoblasts,thereby inhibiting chondrocyte differentiation. At the same time,Runx2 enhances chondrocyte proliferation by inducing Indian porcupine protein( Ihh),and high expression of Ihh induces production of parathyroid hormone like hormone,inhibits Runx2 and chondrocyte maturation,and forms negative feedback regulation of chondrocyte maturation. Runx2 is also one of the genes responsible for the pathogenesis of osteoarthritis. Runx2 is significantly up-regulated in chondrocytes in osteoarthritis cartilage,and the absence of Runx2 in articular chondrocytes may slow the progression of osteoarthritis,which indicates that it is essential for osteoblast differentiation and chondrocyte maturation,and is involved in osteoarthritis.
引文
[1]Komori T.Regulation of osteoblast differentiation by transcription factors[J].J Cell Biochem,2006,99(5):1233-1239.
[2]Otto F,Thornell AP,Crompton T,et al.Cbfa1,a candidate gene for cleidocranial dysplasia syndrome,is essential for osteoblast differentiation and bone development[J].Cell,1997,89(5):765-771.
[3]Kamamoto M,Machida J,Miyachi H,et al.A novel mutation in the C-terminal region of RUNX2/CBFA1 distal to the DNA-binding runt domain in a Japanese patient with cleidocranial dysplasia[J].Int J Oral Maxillofac Surg,2011,40(4):434-437.
[4]Fujiwara M,Tagashira S,Harada H,et al.Isolation and characterization of the distal promoter region of mouse Cbfa1[J].Biochim Biophys Acta,1999,1446(3):265-272.
[5]Okura H,Sato S,Kishikawa S,et al.Runx2-I isoform contributes to fetal bone formation even in the absence of specific N-Terminal amino acids[J].PLo S One,2014,9(9):e108294.
[6]Ying Z,Hassan MQ,Xie RL,et al.Co-stimulation of the bonerelated Runx2 P1 promoter in mesenchymal cells by SP1 and ETStranscription factors at polymorphic purine-rich DNA sequences(Y-repeats)[J].J Biol Chem,2009,284(5):3125.
[7]Sancisi V,Manzotti G,Gugnoni M,et al.RUNX2 expression in thyroid and breast cancer requires the cooperation of three nonredundant enhancers under the control of BRD4 and c-JUN[J].Nucleic Acids Res,2017,45(19):11249-11267.
[8]Hu H,Hilton MJ,Tu X,et al.Sequential roles of Hedgehog and Wnt signaling in osteoblast development[J].Development,2005,132(1):49-60.
[9]Razzaque MS,Soegiarto DW,Chang D,et al.Conditional deletion of Indian hedgehog from collagen type 2alpha1-expressing cells results in abnormal endochondral bone formation[J].J Pathol,2010,207(4):453-461.
[10]Amano K,Densmore MJ,Lanske B.Conditional deletion of indian hedgehog in limb mesenchyme results in complete loss of growth plate formation but allows mature osteoblast differentiation[J].J Bone Miner Res,2015,30(12):2262-2272.
[11]Lenton K,James AW,Manu A,et al.Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling[J].Genesis,2011,49(10):784-796.
[12]Kobayashi H,Gao Y,Ueta C,et al.Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro[J].Biochem Biophys Res Commun,2000,273(2):630-636.
[13]Maeno T,Moriishi T,Yoshida CA,et al.Early onset of Runx2expression caused craniosynostosis,ectopic bone formation,and limb defects[J].Bone,2011,49(4):673-682.
[14]Watney M.Osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13(MMP13)expression in association with transcription factor Runx2 during endochondral ossification[J].J Biol Chem,2012,287(40):33179-33190.
[15]Kawane T,Komori H,Liu W,et al.Dlx5 and Mef2 regulate a novel Runx2 enhancer for osteoblast-specific expression[J].J Bone Miner Res,2015,29(9):1960-1969.
[16]Hilton MJ,Tu X,Wu X,et al.Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation[J].Nat Med,2008,14(3):306-314.
[17]Komori T.Animal models for osteoporosis[J].Eur J Pharmacol,2015,759:287-294.
[18]Komori T.Regulation of osteoblast differentiation by Runx2[J].Adv Exp Med Biol,2010,658(1):43-49.
[19]Moriishi T,Fukuyama R,Ito M,et al.Osteocyte Network;a negative regulatory system for bone mass augmented by the induction of rankl in osteoblasts and sost in osteocytes at unloading[J].PLo S One,2012,7(6):e40143.
[20]Yoshida CA,Komori H,Maruyama Z,et al.SP7 inhibits osteoblast differentiation at a late stage in mice[J].PLo S One,2012,7(3):e32364.
[21]Takarada T,Hinoi E,Nakazato R,et al.An analysis of skeletal development in osteoblast-specific and chondrocyte-specific runtrelated transcription factor-2(Runx2)knockout mice[J].J Bone Miner Res,2013,28(10):2064-2069.
[22]Adhami MD,Rashid H,Chen H,et al.Runx2 activity in committed osteoblasts is not essential for embryonic skeletogenesis[J].Connect Tissue Res,2014,55(Supp 1):102-106.
[23]Chen H,Ghori-Javed FY,Rashid H,et al.Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation[J].J Bone Miner Res,2015,29(12):2653-2665.
[24]Bauer O,Sharir A,Kimura A,et al.Loss of osteoblast Runx3produces severe congenital osteopenia[J].Mol Cell Biol,2015,35(7):1097-1109.
[25]Inada M,Yasui T,Nomura S,et al.Maturational disturbance of chondrocytes in Cbfa1-deficient mice[J].Dev Dyn,2010,214(4):279-290.
[26]Kim IS,Otto F,Zabel B,et al.Regulation of chondrocyte differentiation by Cbfa1[J].Mech Dev,1999,80(2):159-170.
[27]Komori T.Roles of Runx2 in Skeletal Development[J].Adv Exp Med Biol,2017,962:83-93.
[28]Himeno M,Enomoto H,Liu W,et al.Impaired vascular invasion of Cbfa1-deficient cartilage engrafted in the spleen[J].J Bone Miner Res,2002,17(7):1297-1305.
[29]Liao L,Zhang S,Gu J,et al.Deletion of Runx2 in articular chondrocytes decelerates the progression of DMM-induced osteoarthritis in adult mice[J].Sci Rep,2017,7(1):2371.
[30]Hirata M,Kugimiya F,Fukai A,et al.C/EBPβand RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2αas the inducer in chondrocytes[J].Hum Mol Genet,2012,21(5):1111-1123.
[31]Terauchi K,Kobayashi H,Yatabe K,et al.The NAD-dependent deacetylase Sirtuin-1 regulates the expression of osteogenic transcriptional activator runt-related transcription factor 2(Runx2)and production of matrix metalloproteinase(MMP)-13 in chondrocytes in osteoarthritis[J].Int J Mol Sci,2016,17(7).pii:E1019.
[32]Lu J,Sun Y,Ge Q,et al.Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis[J].Bmc Musculoskelet Disord,2014,15:438.
[33]Casta1o-Betancourt MC,Evans DS,Ramos YFM,et al.Novel genetic variants for cartilage thickness and hip osteoarthritis[J].PLo S Genet,2016,12(10):e1006260.
[34]Miller J,Horner A,Stacy T,et al.The core-binding factorβsubunit is required for bone formation and hematopoietic maturation[J].Nat Genet,2002,32(4):645-649.
[35]Chen W,Ma J,Zhu G,et al.Cbfβdeletion in mice recapitulates cleidocranial dysplasia and reveals multiple functions of Cbfβrequired for skeletal development[J].Proc Natl Acad Sci U S A,2014,111(23):8482-8487.
[36]Lim KE,Park NR,Che X,et al.Core binding factorβof osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice[J].J Bone Miner Res,2015,30(4):715-722.
[37]Qin X,Jiang Q,Matsuo Y,et al.Cbfb regulates bone development by stabilizing Runx family proteins[J].J Bone Miner Res,2015,30(4):706-714.
[38]Jiang Q,Qin X,Kawane T,et al.Cbfb2 isoform dominates more potent Cbfb1 and is required for skeletal development[J].J Bone Miner Res,2016,31(7):1391-1404.
[2]Otto F,Thornell AP,Crompton T,et al.Cbfa1,a candidate gene for cleidocranial dysplasia syndrome,is essential for osteoblast differentiation and bone development[J].Cell,1997,89(5):765-771.
[3]Kamamoto M,Machida J,Miyachi H,et al.A novel mutation in the C-terminal region of RUNX2/CBFA1 distal to the DNA-binding runt domain in a Japanese patient with cleidocranial dysplasia[J].Int J Oral Maxillofac Surg,2011,40(4):434-437.
[4]Fujiwara M,Tagashira S,Harada H,et al.Isolation and characterization of the distal promoter region of mouse Cbfa1[J].Biochim Biophys Acta,1999,1446(3):265-272.
[5]Okura H,Sato S,Kishikawa S,et al.Runx2-I isoform contributes to fetal bone formation even in the absence of specific N-Terminal amino acids[J].PLo S One,2014,9(9):e108294.
[6]Ying Z,Hassan MQ,Xie RL,et al.Co-stimulation of the bonerelated Runx2 P1 promoter in mesenchymal cells by SP1 and ETStranscription factors at polymorphic purine-rich DNA sequences(Y-repeats)[J].J Biol Chem,2009,284(5):3125.
[7]Sancisi V,Manzotti G,Gugnoni M,et al.RUNX2 expression in thyroid and breast cancer requires the cooperation of three nonredundant enhancers under the control of BRD4 and c-JUN[J].Nucleic Acids Res,2017,45(19):11249-11267.
[8]Hu H,Hilton MJ,Tu X,et al.Sequential roles of Hedgehog and Wnt signaling in osteoblast development[J].Development,2005,132(1):49-60.
[9]Razzaque MS,Soegiarto DW,Chang D,et al.Conditional deletion of Indian hedgehog from collagen type 2alpha1-expressing cells results in abnormal endochondral bone formation[J].J Pathol,2010,207(4):453-461.
[10]Amano K,Densmore MJ,Lanske B.Conditional deletion of indian hedgehog in limb mesenchyme results in complete loss of growth plate formation but allows mature osteoblast differentiation[J].J Bone Miner Res,2015,30(12):2262-2272.
[11]Lenton K,James AW,Manu A,et al.Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling[J].Genesis,2011,49(10):784-796.
[12]Kobayashi H,Gao Y,Ueta C,et al.Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro[J].Biochem Biophys Res Commun,2000,273(2):630-636.
[13]Maeno T,Moriishi T,Yoshida CA,et al.Early onset of Runx2expression caused craniosynostosis,ectopic bone formation,and limb defects[J].Bone,2011,49(4):673-682.
[14]Watney M.Osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13(MMP13)expression in association with transcription factor Runx2 during endochondral ossification[J].J Biol Chem,2012,287(40):33179-33190.
[15]Kawane T,Komori H,Liu W,et al.Dlx5 and Mef2 regulate a novel Runx2 enhancer for osteoblast-specific expression[J].J Bone Miner Res,2015,29(9):1960-1969.
[16]Hilton MJ,Tu X,Wu X,et al.Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation[J].Nat Med,2008,14(3):306-314.
[17]Komori T.Animal models for osteoporosis[J].Eur J Pharmacol,2015,759:287-294.
[18]Komori T.Regulation of osteoblast differentiation by Runx2[J].Adv Exp Med Biol,2010,658(1):43-49.
[19]Moriishi T,Fukuyama R,Ito M,et al.Osteocyte Network;a negative regulatory system for bone mass augmented by the induction of rankl in osteoblasts and sost in osteocytes at unloading[J].PLo S One,2012,7(6):e40143.
[20]Yoshida CA,Komori H,Maruyama Z,et al.SP7 inhibits osteoblast differentiation at a late stage in mice[J].PLo S One,2012,7(3):e32364.
[21]Takarada T,Hinoi E,Nakazato R,et al.An analysis of skeletal development in osteoblast-specific and chondrocyte-specific runtrelated transcription factor-2(Runx2)knockout mice[J].J Bone Miner Res,2013,28(10):2064-2069.
[22]Adhami MD,Rashid H,Chen H,et al.Runx2 activity in committed osteoblasts is not essential for embryonic skeletogenesis[J].Connect Tissue Res,2014,55(Supp 1):102-106.
[23]Chen H,Ghori-Javed FY,Rashid H,et al.Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation[J].J Bone Miner Res,2015,29(12):2653-2665.
[24]Bauer O,Sharir A,Kimura A,et al.Loss of osteoblast Runx3produces severe congenital osteopenia[J].Mol Cell Biol,2015,35(7):1097-1109.
[25]Inada M,Yasui T,Nomura S,et al.Maturational disturbance of chondrocytes in Cbfa1-deficient mice[J].Dev Dyn,2010,214(4):279-290.
[26]Kim IS,Otto F,Zabel B,et al.Regulation of chondrocyte differentiation by Cbfa1[J].Mech Dev,1999,80(2):159-170.
[27]Komori T.Roles of Runx2 in Skeletal Development[J].Adv Exp Med Biol,2017,962:83-93.
[28]Himeno M,Enomoto H,Liu W,et al.Impaired vascular invasion of Cbfa1-deficient cartilage engrafted in the spleen[J].J Bone Miner Res,2002,17(7):1297-1305.
[29]Liao L,Zhang S,Gu J,et al.Deletion of Runx2 in articular chondrocytes decelerates the progression of DMM-induced osteoarthritis in adult mice[J].Sci Rep,2017,7(1):2371.
[30]Hirata M,Kugimiya F,Fukai A,et al.C/EBPβand RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2αas the inducer in chondrocytes[J].Hum Mol Genet,2012,21(5):1111-1123.
[31]Terauchi K,Kobayashi H,Yatabe K,et al.The NAD-dependent deacetylase Sirtuin-1 regulates the expression of osteogenic transcriptional activator runt-related transcription factor 2(Runx2)and production of matrix metalloproteinase(MMP)-13 in chondrocytes in osteoarthritis[J].Int J Mol Sci,2016,17(7).pii:E1019.
[32]Lu J,Sun Y,Ge Q,et al.Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis[J].Bmc Musculoskelet Disord,2014,15:438.
[33]Casta1o-Betancourt MC,Evans DS,Ramos YFM,et al.Novel genetic variants for cartilage thickness and hip osteoarthritis[J].PLo S Genet,2016,12(10):e1006260.
[34]Miller J,Horner A,Stacy T,et al.The core-binding factorβsubunit is required for bone formation and hematopoietic maturation[J].Nat Genet,2002,32(4):645-649.
[35]Chen W,Ma J,Zhu G,et al.Cbfβdeletion in mice recapitulates cleidocranial dysplasia and reveals multiple functions of Cbfβrequired for skeletal development[J].Proc Natl Acad Sci U S A,2014,111(23):8482-8487.
[36]Lim KE,Park NR,Che X,et al.Core binding factorβof osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice[J].J Bone Miner Res,2015,30(4):715-722.
[37]Qin X,Jiang Q,Matsuo Y,et al.Cbfb regulates bone development by stabilizing Runx family proteins[J].J Bone Miner Res,2015,30(4):706-714.
[38]Jiang Q,Qin X,Kawane T,et al.Cbfb2 isoform dominates more potent Cbfb1 and is required for skeletal development[J].J Bone Miner Res,2016,31(7):1391-1404.
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