关节软骨细胞外基质代谢中Sox9的调控作用
|
摘要
背景:软骨细胞外基质在关节退变中扮演着角色。Sox9是细胞内的重要转录因子,其在关节软骨细胞外基质代谢方面起着重要的调节作用。Sox9能够促进软骨标志物Ⅱ型胶原、蛋白聚糖和Ⅸ型胶原的基因转录,并且能够抑制聚蛋白多糖酶、基质金属蛋白酶的表达,从而维持关节软骨细胞表型。Sox9在骨关节炎早期代偿性表达上调,随着病情的进展Sox9表达下调,因此Sox9是骨关节炎进行性发展的重要靶点。目的:综述Sox9对于关节软骨细胞外基质代谢的作用。方法:第一作者应用计算机检索PubMed和中国知网数据库中关于Sox9的文献,在关键词中以"Sox9,骨关节炎,Ⅱ型胶原,X型胶原,基质金属蛋白酶,聚蛋白多糖酶"为中文检索词,以"Sox9,Osteoarthritis,collagen type II,collagen type X,MMPs,ADAMTS"为英文检索词进行检索。选择65篇文献进行综述。结果与结论:①Sox9是软骨细胞的"主调控因子",是维持软骨细胞表型和软骨稳态的关键转录因子之一,但同时其表达受到精确的调控;②Sox9基因表达调控的具体机制十分复杂,如何上调软骨细胞中Sox9基因的表达有望成为预防和治疗骨关节炎的重要方向之一。
BACKGROUND: Extracellular matrix of chondrocytes plays a role in joint degeneration. Sox9 is an important transcription factor in cells, and plays an important regulatory role in the metabolism of articular cartilage extracellular matrix. It can promote the gene transcription of cartilage markers: type II collagen, proteoglycan and type IX collagen, and inhibit the expression of aggrecanase and matrix metalloproteinase, thereby maintaining the chondrocyte phenotype. Sox9 is up-regulated in compensatory expression in the early stage of osteoarthritis, and down-regulated as the disease progresses. Therefore, Sox9 is an important target for the progressive development of osteoarthritis.OBJECTIVE: To review the role of Sox9 in the metabolism of chondrocyte extracellular matrix.METHODS: A computer-based search was performed in the PubMed and CNKI databases for articles addressing Sox9. The keywords were"Sox9, osteoarthritis, collagen type II, collagen type X, MMPs, ADAMTS" in English and Chinese, respectively. Finally, 65 eligible articles were included to review.RESULTS AND CONCLUSION:(1) Sox9 is the main regulatory factor of chondrocytes and one of the key transcription factors to maintain chondrocyte phenotype and cartilage homeostasis.(2) However, the specific mechanism for the regulation of Sox9 gene expression is very complex at present. How to up-regulate the expression of Sox9 gene in chondrocytes is expected to become an important direction for the prevention and treatment of osteoarthritis
BACKGROUND: Extracellular matrix of chondrocytes plays a role in joint degeneration. Sox9 is an important transcription factor in cells, and plays an important regulatory role in the metabolism of articular cartilage extracellular matrix. It can promote the gene transcription of cartilage markers: type II collagen, proteoglycan and type IX collagen, and inhibit the expression of aggrecanase and matrix metalloproteinase, thereby maintaining the chondrocyte phenotype. Sox9 is up-regulated in compensatory expression in the early stage of osteoarthritis, and down-regulated as the disease progresses. Therefore, Sox9 is an important target for the progressive development of osteoarthritis.OBJECTIVE: To review the role of Sox9 in the metabolism of chondrocyte extracellular matrix.METHODS: A computer-based search was performed in the PubMed and CNKI databases for articles addressing Sox9. The keywords were"Sox9, osteoarthritis, collagen type II, collagen type X, MMPs, ADAMTS" in English and Chinese, respectively. Finally, 65 eligible articles were included to review.RESULTS AND CONCLUSION:(1) Sox9 is the main regulatory factor of chondrocytes and one of the key transcription factors to maintain chondrocyte phenotype and cartilage homeostasis.(2) However, the specific mechanism for the regulation of Sox9 gene expression is very complex at present. How to up-regulate the expression of Sox9 gene in chondrocytes is expected to become an important direction for the prevention and treatment of osteoarthritis
引文
[1]Lefebvre V,Dvir-Ginzberg M.SOX9 and the many facets of its regulation in the chondrocyte lineage.Connect Tissue Res.2016;58(1):2-14.
[2]Südbeck P,Scherer G.Two independent nuclear localization signals are present in the DNA-binding high-mobility group domains of SRY and SOX9.J Biol Chem.1997;272(44):27848-27852.
[3]冀全博.ADAMTS调控骨关节炎软骨退变基质降解的机制研究[D].北京:解放军医学院,2015.
[4]肖瑜.骨关节炎患者软骨在不同Outerbridge分级中SOX9、RUNX2表达的变化[D].天津:天津医科大学,2016.
[5]卓群豪,张伟娜,李舰,等.膝关节腔内注射Sox9转染骨髓间充质干细胞修复膝关节骨关节炎[J].中国组织工程研究,2017,38(5):736-741.
[6]蒋萍,蔚芃,赵明才,等.I,Ⅱ型胶原蛋白对人软骨细胞生物学特性的影响[J].中国组织工程研究,2014,18(30):4845-4850.
[7]宋晓娣.天然Ⅱ型胶原蛋白抗关节炎功能研究[D].天津:天津科技大学,2013.
[8]Lugo JP,Saiyed ZM,Lane NE.Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms:A muhicenter randomized,double-blind,placebo-controlled study.Nutr J.2016;15(1):1-15.
[9]Dateki S.ACANmutations as a cause of familial short stature.Clin Pediatr Endocrinol.2017;26(3):119-125.
[10]Luo Y,Sinkeviciute D,He Y,et al.The minor collagens in articular cartilage.Protein Cell.2017;8(8):560-572.
[11]Wu JJ,Woods PE,Eyre DR.Identification of cross-linking sites in bovine cartilage type IX collagen reveals an antiparallel type II-type IX molecular relationship and type IXto type IX bonding.J Biol Chem.1992;267(32):23007-230014.
[12]Alizadeh BZ,Njajou OT,Bijkerk C,et al.Evidence for a role of the genomic region of the gene encoding for the alpha1 chain of type IX collagen(COL9A1)in hip osteoarthritis:Apopulation-based study.Arthritis Rheum.2005;52(5):1437-1442.
[13]史晓薇,郭雄.COL9A1基因多态性与儿童大骨节病的关联分析[J].中国妇幼健康研究,2016,27(5):556-557.
[14]陈崇伟,卫小春,向川,等.骨性关节炎关节软骨内Ⅰ、Ⅱ、Ⅲ型胶原表型的实验研究[J].山西医科大学学报,2006,37(3):248-251.
[15]Bell DM,Leung KK,Wheatley SC,et al.SOX9 directly regulates the type-II collagen gene.Nat Genet.1997;16(2):174-180.
[16]Yasuda H,Oh CD,Chen D,et al.A Novel Regulatory Mechanism of mType II Collagen Expression via a SOX9-dependent Enhancer in Intron 6.J Biol Chem.2017;292(2):528-538.
[17]Otero M,Peng H,El Hachem K,et al.ELF3 modulates type IIcollagen gene(COL2A1)transcription in chondrocytes by Inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity.Connect Tissue Res.2017;58(1):15-26.
[18]Han Y,Lefebvre V.L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer.Mol Cell Biol.2008;28(16):4999-5013.
[19]Zhang P,Jimenez SA,Stokes DG.Regulation of human COL9A1 gene expression.Activation of the proximal promoter region by SOX9.J Biol Chem.2003;278(1):117-123.
[20]Moulin D,Salone V,Koufany M,et al.MicroRNA-29b contributes to collagens imbalance in human osteoarthritic and dedifferentiated articular chondrocytes.Biomed Res Int.2017;2017:9792512.
[21]Le LT,Swingler TE,Crowe N,et al.The microRNA-29 family in cartilage homeostasis and osteoarthritis.J Mol Med(Berl).2016;94(5):583-596.
[22]Zhang Q,Ji Q,Wang X,et al.SOX9 is a regulator of ADAMTSs-induced cartilage degeneration at the early stage of human osteoarthritis.Osteoarthritis Cartilage.2015;23(12):2259-2268.
[23]Wei F,Zhou J,Wei X,et al.Activation of Indian Hedgehog Promotes Chondrocyte Hypertrophy and Upregulation of MMP-13 in Human Osteoarthritic Cartilage.Osteoarthritis Cartilage.2012;20(7):755-763.
[24]Li H,Wang D,Yuan Y,et al.New insights on the MMP-13regulatory network in the pathogenesis of early osteoarthritis.Arthritis Res Ther.2017;19:248.
[25]Yun K,Im SH.Transcriptional regulation of MMP13 by Lef1 in chondrocytes.Biochem Biophys Res Commun.2007;364(4):1009-1014.
[26]唐芳,马武开,姚血明.Wnt/β-catenin信号通路与骨关节炎[J].风湿病与关节炎,2014,3(2):70-73.
[27]Topol L,Chen W,Song H,et al.Sox9 inhibits wnt signaling by promotingβ-catenin phosphorylation in the nucleus.J Biol Chem.2009;284(5):3323-3333.
[28]庞金辉,刘明轩,石文俊,等.X型胶原在膝骨关节炎软骨中的表达[J].实用临床医药杂志,2012,16(15):44-46.
[29]van der Kraan PM,Stoop R,Meijers TH,et al.Expression of type X collagen in young and old C57Bl/6 and Balb/c mice.Relation with articular cartilage degeneration.Osteoarthritis Cartilage.2001;9(2):92-100.
[30]Amano K,Densmore M,Nishimura R,et al.Indian Hedgehog Signaling Regulates Transcription and Expression of Collagen Type X via Runx2/Smads Interactions.J Biol Chem.2014;289(36):24898-24910.
[31]Li F,Lu Y,Ding M,et al.Runx2 contributes to murine Col10a1gene regulation through direct interaction with its cis-enhancer.J Bone Miner Res.2011;26(12):2899-2910.
[32]Zhou G,Zheng Q,Engin F,et al.Dominance of SOX9 function over RUNX2 during skeletogenesis.Proc Natl Acad Sci U S A.2006;103(50):19004-19009.
[33]Lengner CJ,Hassan MQ,Serra RW,et al.Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation.JBiol Chem.2005;280(16):15872-15879.
[34]Caron MM,Emans PJ,Surtel DA,et al.BAPX-1/NKX-3.2 acts as a chondrocyte hypertrophy molecular switch in osteoarthritis.Arthritis Rheumatol.2015;67(11):2944-2956.
[35]Yamashita S,Andoh M,Ueno-Kudoh H,et al.Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes.Exp Cell Res.2009;315(13):2231-2240.
[36]Yang L,Tsang KY,Tang HC,et al.Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation.Proc Natl Acad Sci U S A.2014;111(33):12097-12102.
[37]Akiyama H,Chaboissier MC,Martin JF,et al.The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6.Genes Dev.2002;16(21):2813-2828.
[38]Amarilio R,Viukov SV,Sharir A,et al.HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis.Development.2007;134(21):3917-3928.
[39]Ushita M,Saito T,Ikeda T,et al.Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells.Osteoarthritis Cartilage.2009;17(8):1065-1077.
[40]Chen S,Tao J,Bae Y,et al.Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9.J Bone Miner Res.2013;28(3):649-659.
[41]Ushita M,Saito T,Ikeda T,et al.Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells.Osteoarthritis Cartilage.2009;17:1065-1075.
[42]Duan L,Liang Y,Ma B,et al.Epigenetic regulation in chondrocyte phenotype maintenance for cell-based cartilage repair.Am J Transl Res.2015;7(11):2127-2140.
[43]Kim KI,Park YS,Im GI.Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage.J Bone Miner Res.2013;28(5):1050-1060.
[44]Zhang W,Cheng P,Hu W,et al.Inhibition of microRNA-384-5p alleviates osteoarthritis through its effects on inhibiting apoptosis of cartilage cells via the NF-κBsignaling pathway by targeting SOX9.Cancer Gene Ther.2018;25(11-12):326-338.
[45]康菲,杨波,闫演飞,等.miR-145在间充质干细胞来源软骨细胞肥大化中的作用[J].第三军医大学学报,2013,35(11):1058-1061.
[46]Martinez-Sanchez A,Dudek KA,Murphy CL.Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145(miRNA-145).J Biol Chem.2011;287(2):916-924.
[47]Wa Q,He P,Huang S,et al.miR-30b regulates chondrogenic differentiation of mouse embryo-derived stem cells by targeting SOX9.Exp Ther Med.2017;14(6):6131-6137.
[48]Cen X,Huang XQ,Sun WT,et al.Long noncoding RNAs:a new regulatory code in osteoarthritis.Am J Transl Res.2017;9(11):4747-4755.
[49]Wang L,Yu X,Zhang Z,et al.Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9.J Exp Clin Cancer Res.2017;36(1):182.
[50]Feng L,Shi L,Lu YF,et al.Linc-ROR Promotes Osteogenic Differentiation of Mesenchymal Stem Cells by Functioning as a Competing Endogenous RNA for miR-138 and miR-145.Mol Ther Nucleic Acids.2018;11:345-353.
[51]Chen LY,Lotz M,Terkeltaub R,et al.Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes.JBiol Chem.2018;293(31):12259-12270.
[52]Bar Oz M,Kumar A,Elayyan J,et al.Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes.Aging Cell.2016;15(3):499-508.
[53]伍平.SIRT1在骨关节炎关节软骨中的表达及其意义[D].长沙:中南大学,2010.
[54]Bar Oz M,Kumar A,Elayyan J,et al.Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes.Aging Cell.2016;15(3):499-508.
[55]Huang W,Zhou X,Lefebvre V,et al.Phosphorylation of SOX9by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.Mol Cell Biol.2000;20(11):4149-4158.
[56]Kamachi Y,Kondoh H.Sox proteins:regulators of cell fate specification and differentiation.Development.2013;140(20):4129-4144.
[57]Malki S,Nef S,Notarnicola C,et al.Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation.EMBO J.2005;24(10):1798-1809.
[58]Ito T,Yadav N,Lee J,et al.Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification.BMCDev Biol.2009.
[59]Akiyama H,Lyons JP,Mori-Akiyama Y,et al.Interactions between Sox9 and beta-catenin control chondrocyte differentiation.Genes Dev.2004;18(9):1072-1087.
[60]Flotho A,Melchior F.Sumoylation:a regulatory protein modification in health and disease.Annu Rev Biochem.2013;82:357-385.
[61]Oh HJ,Kido T,Lau YF.PIAS1 interacts with and represses SOX9 transactivation activity.Mol Reprod Dev.2007;74(11):1446-1455.
[62]Hattori T,Eberspaecher H,Lu J,et al.Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9.J Biol Chem.2006;281(20):14417-14428.
[63]Hattori T,Eberspaecher H,Lu J,et al.Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9.J Biol Chem.2006;281(20):14417-14428.
[64]Hattori T,Kishino T,Stephen S,et al.E6-AP/UBE3A protein acts as a ubiquitin ligase toward SOX9 protein.J Biol Chem.2013;288(49):35138-35148.
[65]Akiyama H,Kamitani T,Yang X,et al.The transcription factor Sox9 is degraded by the ubiquitin-proteasome system and stabilized by a mutation in a ubiquitin-target site.Matrix Biol.2005;23(8):499-505.
[2]Südbeck P,Scherer G.Two independent nuclear localization signals are present in the DNA-binding high-mobility group domains of SRY and SOX9.J Biol Chem.1997;272(44):27848-27852.
[3]冀全博.ADAMTS调控骨关节炎软骨退变基质降解的机制研究[D].北京:解放军医学院,2015.
[4]肖瑜.骨关节炎患者软骨在不同Outerbridge分级中SOX9、RUNX2表达的变化[D].天津:天津医科大学,2016.
[5]卓群豪,张伟娜,李舰,等.膝关节腔内注射Sox9转染骨髓间充质干细胞修复膝关节骨关节炎[J].中国组织工程研究,2017,38(5):736-741.
[6]蒋萍,蔚芃,赵明才,等.I,Ⅱ型胶原蛋白对人软骨细胞生物学特性的影响[J].中国组织工程研究,2014,18(30):4845-4850.
[7]宋晓娣.天然Ⅱ型胶原蛋白抗关节炎功能研究[D].天津:天津科技大学,2013.
[8]Lugo JP,Saiyed ZM,Lane NE.Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms:A muhicenter randomized,double-blind,placebo-controlled study.Nutr J.2016;15(1):1-15.
[9]Dateki S.ACANmutations as a cause of familial short stature.Clin Pediatr Endocrinol.2017;26(3):119-125.
[10]Luo Y,Sinkeviciute D,He Y,et al.The minor collagens in articular cartilage.Protein Cell.2017;8(8):560-572.
[11]Wu JJ,Woods PE,Eyre DR.Identification of cross-linking sites in bovine cartilage type IX collagen reveals an antiparallel type II-type IX molecular relationship and type IXto type IX bonding.J Biol Chem.1992;267(32):23007-230014.
[12]Alizadeh BZ,Njajou OT,Bijkerk C,et al.Evidence for a role of the genomic region of the gene encoding for the alpha1 chain of type IX collagen(COL9A1)in hip osteoarthritis:Apopulation-based study.Arthritis Rheum.2005;52(5):1437-1442.
[13]史晓薇,郭雄.COL9A1基因多态性与儿童大骨节病的关联分析[J].中国妇幼健康研究,2016,27(5):556-557.
[14]陈崇伟,卫小春,向川,等.骨性关节炎关节软骨内Ⅰ、Ⅱ、Ⅲ型胶原表型的实验研究[J].山西医科大学学报,2006,37(3):248-251.
[15]Bell DM,Leung KK,Wheatley SC,et al.SOX9 directly regulates the type-II collagen gene.Nat Genet.1997;16(2):174-180.
[16]Yasuda H,Oh CD,Chen D,et al.A Novel Regulatory Mechanism of mType II Collagen Expression via a SOX9-dependent Enhancer in Intron 6.J Biol Chem.2017;292(2):528-538.
[17]Otero M,Peng H,El Hachem K,et al.ELF3 modulates type IIcollagen gene(COL2A1)transcription in chondrocytes by Inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity.Connect Tissue Res.2017;58(1):15-26.
[18]Han Y,Lefebvre V.L-Sox5 and Sox6 drive expression of the aggrecan gene in cartilage by securing binding of Sox9 to a far-upstream enhancer.Mol Cell Biol.2008;28(16):4999-5013.
[19]Zhang P,Jimenez SA,Stokes DG.Regulation of human COL9A1 gene expression.Activation of the proximal promoter region by SOX9.J Biol Chem.2003;278(1):117-123.
[20]Moulin D,Salone V,Koufany M,et al.MicroRNA-29b contributes to collagens imbalance in human osteoarthritic and dedifferentiated articular chondrocytes.Biomed Res Int.2017;2017:9792512.
[21]Le LT,Swingler TE,Crowe N,et al.The microRNA-29 family in cartilage homeostasis and osteoarthritis.J Mol Med(Berl).2016;94(5):583-596.
[22]Zhang Q,Ji Q,Wang X,et al.SOX9 is a regulator of ADAMTSs-induced cartilage degeneration at the early stage of human osteoarthritis.Osteoarthritis Cartilage.2015;23(12):2259-2268.
[23]Wei F,Zhou J,Wei X,et al.Activation of Indian Hedgehog Promotes Chondrocyte Hypertrophy and Upregulation of MMP-13 in Human Osteoarthritic Cartilage.Osteoarthritis Cartilage.2012;20(7):755-763.
[24]Li H,Wang D,Yuan Y,et al.New insights on the MMP-13regulatory network in the pathogenesis of early osteoarthritis.Arthritis Res Ther.2017;19:248.
[25]Yun K,Im SH.Transcriptional regulation of MMP13 by Lef1 in chondrocytes.Biochem Biophys Res Commun.2007;364(4):1009-1014.
[26]唐芳,马武开,姚血明.Wnt/β-catenin信号通路与骨关节炎[J].风湿病与关节炎,2014,3(2):70-73.
[27]Topol L,Chen W,Song H,et al.Sox9 inhibits wnt signaling by promotingβ-catenin phosphorylation in the nucleus.J Biol Chem.2009;284(5):3323-3333.
[28]庞金辉,刘明轩,石文俊,等.X型胶原在膝骨关节炎软骨中的表达[J].实用临床医药杂志,2012,16(15):44-46.
[29]van der Kraan PM,Stoop R,Meijers TH,et al.Expression of type X collagen in young and old C57Bl/6 and Balb/c mice.Relation with articular cartilage degeneration.Osteoarthritis Cartilage.2001;9(2):92-100.
[30]Amano K,Densmore M,Nishimura R,et al.Indian Hedgehog Signaling Regulates Transcription and Expression of Collagen Type X via Runx2/Smads Interactions.J Biol Chem.2014;289(36):24898-24910.
[31]Li F,Lu Y,Ding M,et al.Runx2 contributes to murine Col10a1gene regulation through direct interaction with its cis-enhancer.J Bone Miner Res.2011;26(12):2899-2910.
[32]Zhou G,Zheng Q,Engin F,et al.Dominance of SOX9 function over RUNX2 during skeletogenesis.Proc Natl Acad Sci U S A.2006;103(50):19004-19009.
[33]Lengner CJ,Hassan MQ,Serra RW,et al.Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation.JBiol Chem.2005;280(16):15872-15879.
[34]Caron MM,Emans PJ,Surtel DA,et al.BAPX-1/NKX-3.2 acts as a chondrocyte hypertrophy molecular switch in osteoarthritis.Arthritis Rheumatol.2015;67(11):2944-2956.
[35]Yamashita S,Andoh M,Ueno-Kudoh H,et al.Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes.Exp Cell Res.2009;315(13):2231-2240.
[36]Yang L,Tsang KY,Tang HC,et al.Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation.Proc Natl Acad Sci U S A.2014;111(33):12097-12102.
[37]Akiyama H,Chaboissier MC,Martin JF,et al.The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6.Genes Dev.2002;16(21):2813-2828.
[38]Amarilio R,Viukov SV,Sharir A,et al.HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis.Development.2007;134(21):3917-3928.
[39]Ushita M,Saito T,Ikeda T,et al.Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells.Osteoarthritis Cartilage.2009;17(8):1065-1077.
[40]Chen S,Tao J,Bae Y,et al.Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9.J Bone Miner Res.2013;28(3):649-659.
[41]Ushita M,Saito T,Ikeda T,et al.Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells.Osteoarthritis Cartilage.2009;17:1065-1075.
[42]Duan L,Liang Y,Ma B,et al.Epigenetic regulation in chondrocyte phenotype maintenance for cell-based cartilage repair.Am J Transl Res.2015;7(11):2127-2140.
[43]Kim KI,Park YS,Im GI.Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage.J Bone Miner Res.2013;28(5):1050-1060.
[44]Zhang W,Cheng P,Hu W,et al.Inhibition of microRNA-384-5p alleviates osteoarthritis through its effects on inhibiting apoptosis of cartilage cells via the NF-κBsignaling pathway by targeting SOX9.Cancer Gene Ther.2018;25(11-12):326-338.
[45]康菲,杨波,闫演飞,等.miR-145在间充质干细胞来源软骨细胞肥大化中的作用[J].第三军医大学学报,2013,35(11):1058-1061.
[46]Martinez-Sanchez A,Dudek KA,Murphy CL.Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145(miRNA-145).J Biol Chem.2011;287(2):916-924.
[47]Wa Q,He P,Huang S,et al.miR-30b regulates chondrogenic differentiation of mouse embryo-derived stem cells by targeting SOX9.Exp Ther Med.2017;14(6):6131-6137.
[48]Cen X,Huang XQ,Sun WT,et al.Long noncoding RNAs:a new regulatory code in osteoarthritis.Am J Transl Res.2017;9(11):4747-4755.
[49]Wang L,Yu X,Zhang Z,et al.Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9.J Exp Clin Cancer Res.2017;36(1):182.
[50]Feng L,Shi L,Lu YF,et al.Linc-ROR Promotes Osteogenic Differentiation of Mesenchymal Stem Cells by Functioning as a Competing Endogenous RNA for miR-138 and miR-145.Mol Ther Nucleic Acids.2018;11:345-353.
[51]Chen LY,Lotz M,Terkeltaub R,et al.Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes.JBiol Chem.2018;293(31):12259-12270.
[52]Bar Oz M,Kumar A,Elayyan J,et al.Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes.Aging Cell.2016;15(3):499-508.
[53]伍平.SIRT1在骨关节炎关节软骨中的表达及其意义[D].长沙:中南大学,2010.
[54]Bar Oz M,Kumar A,Elayyan J,et al.Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes.Aging Cell.2016;15(3):499-508.
[55]Huang W,Zhou X,Lefebvre V,et al.Phosphorylation of SOX9by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.Mol Cell Biol.2000;20(11):4149-4158.
[56]Kamachi Y,Kondoh H.Sox proteins:regulators of cell fate specification and differentiation.Development.2013;140(20):4129-4144.
[57]Malki S,Nef S,Notarnicola C,et al.Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation.EMBO J.2005;24(10):1798-1809.
[58]Ito T,Yadav N,Lee J,et al.Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification.BMCDev Biol.2009.
[59]Akiyama H,Lyons JP,Mori-Akiyama Y,et al.Interactions between Sox9 and beta-catenin control chondrocyte differentiation.Genes Dev.2004;18(9):1072-1087.
[60]Flotho A,Melchior F.Sumoylation:a regulatory protein modification in health and disease.Annu Rev Biochem.2013;82:357-385.
[61]Oh HJ,Kido T,Lau YF.PIAS1 interacts with and represses SOX9 transactivation activity.Mol Reprod Dev.2007;74(11):1446-1455.
[62]Hattori T,Eberspaecher H,Lu J,et al.Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9.J Biol Chem.2006;281(20):14417-14428.
[63]Hattori T,Eberspaecher H,Lu J,et al.Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9.J Biol Chem.2006;281(20):14417-14428.
[64]Hattori T,Kishino T,Stephen S,et al.E6-AP/UBE3A protein acts as a ubiquitin ligase toward SOX9 protein.J Biol Chem.2013;288(49):35138-35148.
[65]Akiyama H,Kamitani T,Yang X,et al.The transcription factor Sox9 is degraded by the ubiquitin-proteasome system and stabilized by a mutation in a ubiquitin-target site.Matrix Biol.2005;23(8):499-505.