骨质疏松症的表观遗传学调控
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摘要
表观遗传学修饰是指在DNA序列未变化的情况下发生的可遗传的基因表达的变化,主要机制包括DNA甲基化、组蛋白修饰、非编码RNAs、染色质修饰等。骨质疏松症(osteoporosis,OP)是一种最常见的骨组织疾病,其特征是骨强度下降和微细结构破坏,患者发生骨折的风险增加,通常是由于新骨形成不足以补偿过度的骨吸收。目前认为表观遗传学调控在OP的发生和发展中起重要意义。表观遗传学修饰广泛参与成骨细胞和破骨细胞分化及成骨-骨细胞转变过程中重要基因表达的调控及成骨细胞和破骨细胞的交互作用。针对表观遗传学机制的药物初步显示了在OP治疗中的前景。
Epigenetic modification indicates the inheritable alteration of gene expression without changing DNA sequence,including DNA methylation,histone modifications,non-coding RNAs and chromatin modifications etc.Osteoporosis is the most common bone disease characterized by decreased bone strength and bone micro-architectural deterioration,an increased risk of fractures.Nowadays it is well accepted that epigenetic regulation is deeply involved in the occurrence and development of osteoporosis.Epigenetic modification regulates the expression of important genes in the differentiation of osteoblasts and osteoclasts and osteoblast-to-osteocyte transition,even the crosstalk between osteoblasts and osteoclasts.Epigenetically active drugs have already shown potential for the treatment of osteoporosis.
Epigenetic modification indicates the inheritable alteration of gene expression without changing DNA sequence,including DNA methylation,histone modifications,non-coding RNAs and chromatin modifications etc.Osteoporosis is the most common bone disease characterized by decreased bone strength and bone micro-architectural deterioration,an increased risk of fractures.Nowadays it is well accepted that epigenetic regulation is deeply involved in the occurrence and development of osteoporosis.Epigenetic modification regulates the expression of important genes in the differentiation of osteoblasts and osteoclasts and osteoblast-to-osteocyte transition,even the crosstalk between osteoblasts and osteoclasts.Epigenetically active drugs have already shown potential for the treatment of osteoporosis.
引文
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[16]Chen J,Qiu,M,Dou C,et al.MicroRNAs in bone balance and osteoporosis[J].Drug Dev Res,2015,76:235-245.
[17]Li H,Li T,Fan J,et al.miR-216a rescues dexamethasone suppression of osteogenesis,promotes osteoblast differentiation and enhances bone formation,by regulating c-Cbl-mediated PI3K/AKT pathway[J].Cell Death Differ,2015,22:1935-1945.
[18]Du F,Wu H,Zhou Z,et al.microRNA-375 inhibits osteogenic differentiation by targeting runt-related transcription factor 2[J].Exp Ther Med,2015,10:207-212.
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[20]Vimalraj S,Partridge NC,Selvamurugan NA,et al.Positive role of microRNA-15b on regulation of osteoblast differentiation[J].J Cell Physiol,2014,229:1236-1244.
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[23]Kim K,Kim JH,Kim I,et al.MicroRNA-26a regulates RANKL-induced osteoclast formation[J].Mol Cells,2015,38:75-80.
[24]Dou C,Zhang C,Kang F,et al.miR-7b directly targets DC-STAMP causing suppression of NFATc1 and cFos signaling during osteoclast fusion and differentiation[J].Biochim Biophys Acta,2014,1839:1084-1096.
[25]Zhang JG,Tan LJ,Xu C,et al.Integrative analysis of transcriptomic and epigenomic data to reveal regulation patterns for BMD variation[J].PLo S One,2015,10:147-152.
[26]Ye L,Fan Z,Yu B,et al.Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs[J].Cell Stem Cell,2012,11:50-61.
[27]Jing H,Liao L,An Y,et al.Suppression of EZH2prevents the shift of osteoporotic MSC fate to adipocyte and enhances bone formation during osteoporosis[J].Mol Ther,2016,24:217-222.
[28]Seeliger C,Karpinski K,Haug AT,et al.Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures[J].J Bone Miner Res,2014,29:1718-1728.
[29]Hackl M,Heilmeier U,Weilner S,et al.Circulating microRNAs as novel biomarkers for bone diseasesComplex signatures for multifactorial diseases?[J].Mol Cell Endocrinol,2016,432:83-95.
[30]Panach L,Mifsut D,Tarin JJ,et al.Serum circulating microRNAs as biomarkers of osteoporotic fracture[J].Calcif Tissue Int,2015,97:495-505.
[31]Guo DW,Han YX,Cong L,et al.Resveratrol prevents osteoporosis in ovariectomized rats by regulating microRNA-338-3p[J].Mol Med Rep,2015,12:2098-2106.
[32]Baertschi S,Baur N,Lueders-Lefevre V,et al.ClassⅠandⅡa histone deacetylases have opposite effects on sclerostin gene regulation[J].J Biol Chem,2014,289:24995-25009.
[33]Kim HN,Lee JH,Bae SC,et al.Histone deacetylase inhibitor MS-275 stimulates bone formation in part by enhancing Dhx36-mediated TNAP transcription[J].J Bone Miner Res,2011,26:2161-2173.
[34]Meng S,Zhang L,Tang Y,et al.BET inhibitor JQ1blocks inflammation and bone destruction[J].J Dent Res,2014,93:657-662.
[35]Gjoksi B,Ghayor C,Siegenthaler B,et al.The epigenetically active small chemical N-methyl pyrrolidone(NMP)prevents estrogen depletion induced osteoporosis[J].Bone,2015,78:114-121.
[36]Park-Min KH,Lim E,Lee MJ,et al.Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation[J].Nat Commun,2014,5:5418.
[37]Lamoureux F,Baud'huin M,Rodriguez Calleja L,et al.Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle[J].Nat Commun,2014,5:3511.
[38]Miguel BS,Ghayor C,Ehrbar M,et al.N-methyl pyrrolidone as a potent bone morphogenetic protein enhancer for bone tissue regeneration[J].Tissue Eng Part A,2009,15:2955-2963.
[39]Ghayor C,Gjoksi B,Siegenthaler B,et al.N-methyl pyrrolidone(NMP)inhibits lipopolysaccharide-induced inflammation by suppressing NF-kappa B signaling[J].Inflamm Res,2015,64:527-536.
[2]Feinberg A.DNA methylation in cancer:three decades of discovery[J].Genome Med,2014,6:36.
[3]Zhang RP,Shao JZ,Xiang LX.GADD45A protein plays an essential role in active DNA demethylation during terminal osteogenic differentiation of adipose-derived mesenchymal stem cells[J].J Biol Chem,2011,286:41083-41094.
[4]Cho YD,Yoon WJ,Kim WJ,et al.Epigenetic modifications and canonical wingless/int-1 class(WNT)signaling enable trans-differentiation of non-osteogenic cells into osteoblasts[J].J Biol Chem,2014,289:20120-20128.
[5]Delgado-Calle J,Sa1udo C,Fernández AF,et al.Role of DNA methylation in the regulation of the RANKL-OPG system in human bone[J].Epigenetics,2012,7:83-91.
[6]Nishikawa K,Iwamoto Y,Kobayashi Y,et al.DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway[J].Nat Med,2015,21:281-287.
[7]Delgado-Calle J,Sa1udo C,Bolado A,et al.DNA methylation contributes to the regulation of sclerostin expression in human osreocytes[J].J Bone Miner Res,2012,27:926-937.
[8]Zhang P,Liu Y,Jin C,et al.Histone H3K9 acetyltransferase PCAF is essential for osteogenic differentiation through bone morphogenetic protein signaling and may be involved in osteoporosis[J].Stem Cells,2016,34:2332-2341.
[9]Deng P,Chen QM,Hong C,et al.Histone methyltransferases and demethylases:regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells[J].Int J Oral Sci,2015,7:197-204.
[10]Rojas A,Aguilar R,Henriquez B,et al.Epigenetic control of the bone-master Runx2 gene during osteoblast-lineage commitment by the histone demethylase JARID1B/KDM5B[J].J Biol Chem,2015,290:28329-28342.
[11]Veronica JP,Claes W.Non-coding RNAs as direct and indirect modulators of epigenetic regulation[J].Epigenetics,2014,9:3-12.
[12]Zhu L,Xu PC.Down regulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression[J].Biochem Biophys Res Commun,2013,432:612-617.
[13]Tong X,Gu PC,Xu SZ,et al.Long non-coding RNA-DANCR in human circulating monocytes:A potential biomarker associated with postmenopausal osteoporosis[J].Biosci Biotechnol Biochem,2015,79:732-737.
[14]Garmilla-Ezquerra P,Sanudo C,Delgado-Calle J,et al.Analysis of the bone microRNome in osteoporotic fractures[J].Calcif Tissue Int,2015,96:30-37.
[15]Weilner S,Skalicky S,Salzer B,et al.Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation[J].Bone,2015,79:43-51.
[16]Chen J,Qiu,M,Dou C,et al.MicroRNAs in bone balance and osteoporosis[J].Drug Dev Res,2015,76:235-245.
[17]Li H,Li T,Fan J,et al.miR-216a rescues dexamethasone suppression of osteogenesis,promotes osteoblast differentiation and enhances bone formation,by regulating c-Cbl-mediated PI3K/AKT pathway[J].Cell Death Differ,2015,22:1935-1945.
[18]Du F,Wu H,Zhou Z,et al.microRNA-375 inhibits osteogenic differentiation by targeting runt-related transcription factor 2[J].Exp Ther Med,2015,10:207-212.
[19]Qadir AS,Um S,Lee H,et al.miR-124 negatively regulates osteogenic differentiation and in vivo bone formation of mesenchymal stem cells[J].J Cell Biochem,2015,116:730-742.
[20]Vimalraj S,Partridge NC,Selvamurugan NA,et al.Positive role of microRNA-15b on regulation of osteoblast differentiation[J].J Cell Physiol,2014,229:1236-1244.
[21]Ke K,Sul OJ,Rajasekaran M,et al.MicroRNA-183increases osteoclastogenesis by repressing heme oxygenase-1[J].Bone,2015,81:237-246.
[22]Zhao C,Sun W,Zhang P,et al.miR-214 promotes osteoclastogenesis by targeting Pten/PI3k/Akt pathway[J].RNA Biol,2015,12:343-353.
[23]Kim K,Kim JH,Kim I,et al.MicroRNA-26a regulates RANKL-induced osteoclast formation[J].Mol Cells,2015,38:75-80.
[24]Dou C,Zhang C,Kang F,et al.miR-7b directly targets DC-STAMP causing suppression of NFATc1 and cFos signaling during osteoclast fusion and differentiation[J].Biochim Biophys Acta,2014,1839:1084-1096.
[25]Zhang JG,Tan LJ,Xu C,et al.Integrative analysis of transcriptomic and epigenomic data to reveal regulation patterns for BMD variation[J].PLo S One,2015,10:147-152.
[26]Ye L,Fan Z,Yu B,et al.Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs[J].Cell Stem Cell,2012,11:50-61.
[27]Jing H,Liao L,An Y,et al.Suppression of EZH2prevents the shift of osteoporotic MSC fate to adipocyte and enhances bone formation during osteoporosis[J].Mol Ther,2016,24:217-222.
[28]Seeliger C,Karpinski K,Haug AT,et al.Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures[J].J Bone Miner Res,2014,29:1718-1728.
[29]Hackl M,Heilmeier U,Weilner S,et al.Circulating microRNAs as novel biomarkers for bone diseasesComplex signatures for multifactorial diseases?[J].Mol Cell Endocrinol,2016,432:83-95.
[30]Panach L,Mifsut D,Tarin JJ,et al.Serum circulating microRNAs as biomarkers of osteoporotic fracture[J].Calcif Tissue Int,2015,97:495-505.
[31]Guo DW,Han YX,Cong L,et al.Resveratrol prevents osteoporosis in ovariectomized rats by regulating microRNA-338-3p[J].Mol Med Rep,2015,12:2098-2106.
[32]Baertschi S,Baur N,Lueders-Lefevre V,et al.ClassⅠandⅡa histone deacetylases have opposite effects on sclerostin gene regulation[J].J Biol Chem,2014,289:24995-25009.
[33]Kim HN,Lee JH,Bae SC,et al.Histone deacetylase inhibitor MS-275 stimulates bone formation in part by enhancing Dhx36-mediated TNAP transcription[J].J Bone Miner Res,2011,26:2161-2173.
[34]Meng S,Zhang L,Tang Y,et al.BET inhibitor JQ1blocks inflammation and bone destruction[J].J Dent Res,2014,93:657-662.
[35]Gjoksi B,Ghayor C,Siegenthaler B,et al.The epigenetically active small chemical N-methyl pyrrolidone(NMP)prevents estrogen depletion induced osteoporosis[J].Bone,2015,78:114-121.
[36]Park-Min KH,Lim E,Lee MJ,et al.Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation[J].Nat Commun,2014,5:5418.
[37]Lamoureux F,Baud'huin M,Rodriguez Calleja L,et al.Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle[J].Nat Commun,2014,5:3511.
[38]Miguel BS,Ghayor C,Ehrbar M,et al.N-methyl pyrrolidone as a potent bone morphogenetic protein enhancer for bone tissue regeneration[J].Tissue Eng Part A,2009,15:2955-2963.
[39]Ghayor C,Gjoksi B,Siegenthaler B,et al.N-methyl pyrrolidone(NMP)inhibits lipopolysaccharide-induced inflammation by suppressing NF-kappa B signaling[J].Inflamm Res,2015,64:527-536.