Long noncoding RNAs: a missing link in osteoporosis

Abstract

Genomic ‘dark matter’ could improve the diagnosis and prognosis of patients with osteoporosis, as well as providing new drug targets for the disease. Only 2.3% of the human genome is translated into protein; the function of the remainder had been unclear, but recent studies suggest some of it provides instructions for making regulators of protein synthesis called long non-coding RNAs (lncRNAs). In this review, Maria Ines Almeida at the University of Porto in Portugal and colleagues explore the role of lncRNAs in bone cell differentiation, metabolism and fracture healing - and describe early studies assessing their role as diagnostic and prognostic biomarkers of osteoporosis. Future advances in genome editing may also provide opportunities to redress the balance between bone production and resorption – something that becomes skewed in osteoporosis - by targeting lncRNAs.

References

[1] Reginster JY, Burlet N. Osteoporosis: a still increasing prevalence. Bone, 2006, 38:4-9

[2] Phetfong J et al. Osteoporosis: the current status of mesenchymal stem cell-based therapy. Cell. Mol. Biol. Lett., 2016, 21:12

[3] Tella SH, Gallagher JC. Prevention and treatment of postmenopausal osteoporosis. J. Steroid Biochem. Mol. Biol., 2014, 142:155-170

[4] Kanis, J.A., McCloskey, E.V., Johansson, H. & Oden, A. Approaches to the targeting of treatment for osteoporosis. Nat. Rev. Rheumatol. 5, 425–31 (2009).

[5] Hernlund E et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch. Osteoporos., 2013, 8

[6] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos. Int., 2006, 17:1726-1733

[7] Harvey N, Dennison E, Cooper C. Osteoporosis: impact on health and economics. Nat. Rev. Rheumatol., 2010, 6:99-105

[8] Qaseem A, Forciea MA, McLean RM, Denberg TD. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann. Intern. Med., 2017, 166:818-839

[9] Eriksen EF, Díez-Pérez A, Boonen S. Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone, 2014, 58:126-135

[10] Liu Y et al. Anabolic agents: what is beyond osteoporosis? Osteoporos. Int., 2018, 29:1009-1022

[11] Azam S et al. Hormone replacement therapy, mammographic density, and breast cancer risk: a cohort study. Cancer Causes Control, 2018, 29:495-505

[12] McNeil M. Menopausal hormone therapy: understanding long-term risks and benefits. J. Am. Med. Assoc., 2017, 318:911-913

[13] Djebali S et al. Landscape of transcription in human cells. Nature, 2012, 489:101-108

[14] Hangauer MJ, Vaughn IW, McManus MT. Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet., 2013, 9:e1003569

[15] Dinger ME, Pang KC, Mercer TR, Mattick JS. Differentiating protein-coding and noncoding RNA: challenges and ambiguities. PLoS Comput. Biol., 2008, 4:e1000176

[16] Carninci P et al. The transcriptional landscape of the mammalian genome. Science, 2005, 309:1559-1563

[17] Hüttenhofer A, Schattner P, Polacek N. Non-coding RNAs: hope or hype? Trends Genet., 2005, 21:289-297

[18] Palazzo AF, Lee ES. Non-coding RNA: what is functional and what is junk? Front. Genet., 2015, 6:2

[19] Almeida MI, Reis RM, Calin GA. MicroRNA history: discovery, recent applications, and next frontiers. Mutat. Res., 2011, 717:1-8

[20] Spizzo R, Almeida MI, Colombatti A, Calin GA. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene, 2012, 31:4577-4587

[21] Dykes IM, Emanueli C. Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genom. Proteom. Bioinforma., 2017, 15:177-186

[22] Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat. Rev. Genet., 2009, 10:155-159

[23] Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell, 2013, 154:26-46

[24] St Laurent G, Wahlestedt C, Kapranov P. The landscape of long noncoding RNA classification. Trends Genet., 2015, 31:239-251

[25] Derrien T et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res., 2012, 22:1775-1789

[26] Sati S, Ghosh S, Jain V, Scaria V, Sengupta S. Genome-wide analysis reveals distinct patterns of epigenetic features in long non-coding RNA loci. Nucleic Acids Res., 2012, 40:10018-10031

[27] Ling H et al. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res., 2013, 23:1446-1461

[28] Fang S et al. NONCODEV5: a comprehensive annotation database for long non-coding RNAs. Nucleic Acids Res., 2018, 46:D308-D314

[29] Golicz AA, Singh MB, Bhalla PL. The long intergenic noncoding RNA (LincRNA) landscape of the soybean genome. Plant Physiol., 2018, 176:2133-2147

[30] Chekanova JA. Long non-coding RNAs and their functions in plants. Curr. Opin. Plant Biol., 2015, 27:207-216

[31] Wu H, Yang L, Chen LL. The diversity of long noncoding RNAs and their generation. Trends Genet., 2017, 33:540-552

[32] Saxena A, Carninci P. Long non-coding RNA modifies chromatin: epigenetic silencing by long non-coding RNAs. BioEssays, 2011, 33:830-839

[33] Han P, Chang CP. Long non-coding RNA and chromatin remodeling. RNA Biol., 2015, 12:1094-1098

[34] Tsai MC et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science, 2010, 329:689-693

[35] Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science, 2008, 322:750-756

[36] Nagano T et al. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science, 2008, 322:1717-1720

[37] Feng J et al. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev., 2006, 20:1470-1484

[38] Yakovchuk P, Goodrich JA, Kugel JF. B2 RNA and Alu RNA repress transcription by disrupting contacts between RNA polymerase II and promoter DNA within assembled complexes. Proc. Natl Acad. Sci. USA, 2009, 106:5569-5574

[39] Mariner PD et al. Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock. Mol. Cell, 2008, 29:499-509

[40] Almeida MI, Reis RM, Calin GA. Decoy activity through microRNAs: the therapeutic implications. Expert. Opin. Biol. Ther., 2012, 12:1153-1159

[41] Yoon JH, Abdelmohsen K, Gorospe M. Posttranscriptional gene regulation by long noncoding RNA. J. Mol. Biol., 2013, 425:3723-3730

[42] Bejerano G et al. Ultraconserved elements in the human genome. Science, 2004, 304:1321-1325

[43] Calin GA et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell., 2007, 12:215-229

[44] Diederichs S. The four dimensions of noncoding RNA conservation. Trends Genet., 2014, 30:121-123

[45] Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP. Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell, 2011, 147:1537-1550

[46] Gu C et al. Long noncoding RNA EBF3-AS promotes neuron apoptosis in Alzheimer’s disease. DNA Cell Biol., 2018, 37:220-226

[47] Li B et al. LncRNA FAL1 promotes cell proliferation and migration by acting as a CeRNA of miR-1236 in hepatocellular carcinoma cells. Life. Sci., 2018, 197:122-129

[48] Wang P, Ren Z, Sun P. Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation. J. Cell. Biochem., 2012, 113:1868-1874

[49] Zheng J et al. lncRNA PVT1 promotes the angiogenesis of vascular endothelial cell by targeting miR‑26b to activate CTGF/ANGPT2. Int. J. Mol. Med., 2018, 42:489-496

[50] Chen L et al. LncRNA GAS5 is a critical regulator of metastasis phenotype of melanoma cells and inhibits tumor growth in vivo. OncoTargets Ther., 2016, 9:4075-4087

[51] Cheng Z et al. The long non-coding RNA uc.4 influences cell differentiation through the TGF-beta signaling pathway. Exp. Mol. Med., 2018, 50

[52] Xu S, Kong D, Chen Q, Ping Y, Pang D. Oncogenic long noncoding RNA landscape in breast cancer. Mol. Cancer, 2017, 16

[53] Yang Z et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann. Surg. Oncol., 2011, 18:1243-1250

[54] Zhang A et al. LncRNA HOTAIR enhances the androgen-receptor-mediated transcriptional program and drives castration-resistant prostate cancer. Cell Rep., 2015, 13:209-221

[55] Wang, W.-J. et al. HDncRNA: a comprehensive database of non-coding RNAs associated with heart diseases. Database 2018, 1–8 (2018).

[56] Guo, C.-C., Jiao, C.-H. & Gao, Z.-M. Silencing of LncRNA BDNF-AS attenuates Aβ25-35-induced neurotoxicity in PC12 cells by suppressing cell apoptosis and oxidative stress. Neurol. Res. 1–10 (2018). https://doi.org/10.1080/01616412.2018.1480921

[57] Valenti, M. T., Dalle Carbonare, L. & Mottes, M. Osteogenic Differentiation in Healthy and Pathological Conditions. Int. J. Mol. Sci. 18, pii: E411 (2016).

[58] You L, Pan L, Chen L, Gu W, Chen J. MiR-27a is essential for the shift from osteogenic differentiation to adipogenic differentiation of mesenchymal stem cells in postmenopausal osteoporosis. Cell. Physiol. Biochem., 2016, 39:253-265

[59] Wang L, Wang Y, Li Z, Li Z, Yu B. Differential expression of long noncoding ribonucleic acids during osteogenic differentiation of human bone marrow mesenchymal stem cells. Int. Orthop., 2015, 39:1013-1019

[60] Zhang W et al. Differential long noncoding RNA/mRNA expression profiling and functional network analysis during osteogenic differentiation of human bone marrow mesenchymal stem cells. Stem Cell Res. Ther., 2017, 8:30

[61] Qiu X et al. The critical role of long noncoding RNA in osteogenic differentiation of human bone marrow mesenchymal. Stem Cells BioMed. Res. Int., 2017, 2017:5045827

[62] Kim M, Yu Y, Moon JH, Koh I, Lee JH. Differential expression profiling of long noncoding RNA and mRNA during osteoblast differentiation in mouse. Int. J. Genom., 2018, 2018:7691794

[63] Zhu L, Xu PC. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem. Biophys. Res. Commun., 2013, 432:612-617

[64] Jia Q, Jiang W, Ni L. Down-regulated non-coding RNA (lncRNA-ANCR) promotes osteogenic differentiation of periodontal ligament stem cells. Arch. Oral Biol., 2015, 60:234-241

[65] Peng W et al. Long noncoding RNA ANCR suppresses bone formation of periodontal ligament stem cells via sponging miRNA-758. Biochem. Biophys. Res. Commun., 2018

[66] Jia Q et al. The regulatory effects of long noncoding RNA-ANCR on dental tissue-derived stem cells. Stem Cells Int., 2016, 2016:3146805

[67] Zhang J, Tao Z, Wang Y. Long non‑coding RNA DANCR regulates the proliferation and osteogenic differentiation of human bone-derived marrow mesenchymal stem cells via the p38 MAPK pathway. Int. J. Mol. Med., 2018, 41:213-219

[68] Wei B, Wei W, Zhao B, Guo X, Liu S. Long non-coding RNA HOTAIR inhibits miR-17-5p to regulate osteogenic differentiation and proliferation in non-traumatic osteonecrosis of femoral head. PLoS One, 2017, 12:e0169097

[69] Jia J et al. MiR-17-5p modulates osteoblastic differentiation and cell proliferation by targeting SMAD7 in non-traumatic osteonecrosis. Exp. Mol. Med., 2014, 46

[70] Kalwa M et al. The lncRNA HOTAIR impacts on mesenchymal stem cells via triple helix formation. Nucleic Acids Res., 2016, 44:10631-10643

[71] Bhan A, Mandal SS. LncRNA HOTAIR: a master regulator of chromatin dynamics and cancer. Biochim. Biophys. Acta, 2015, 1856:151-164

[72] Chen X et al. Long non-coding RNA XIST promotes osteoporosis through inhibiting bone marrow mesenchymal stem cell differentiation. Exp. Ther. Med., 2019, 17:803-811

[73] Montes M et al. The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence. Nat. Commun., 2015, 6

[74] Jin C et al. Inhibition of lncRNA MIR31HG promotes osteogenic differentiation of human adipose-derived stem cells. Stem Cells, 2016, 34:2707-2720

[75] Jin C et al. Long non-coding RNA MIAT knockdown promotes osteogenic differentiation of human adipose-derived stem cells. Cell. Biol. Int., 2017, 41:33-41

[76] Yin C et al. A novel long noncoding RNA AK016739 inhibits osteoblast differentiation and bone formation. J. Cell. Physiol., 2019

[77] Zhu XX et al. Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells. Oncotarget, 2016, 7:63561-63570

[78] Li H, Zhang Z, Chen Z, Zhang D. Osteogenic growth peptide promotes osteogenic differentiation of mesenchymal stem cells mediated by LncRNA AK141205-induced upregulation of CXCL13. Biochem. Biophys. Res. Commun., 2015, 466:82-88

[79] Tian F, Ji XL, Xiao WA, Wang B, Wang F. CXCL13 promotes osteogenic differentiation of mesenchymal stem cells by inhibiting miR-23a expression. Stem Cells Int., 2015, 2015:632305

[80] Jiao H, Xiao E, Graves DT. Diabetes and its effect on bone and fracture healing. Curr. Osteoporos. Rep., 2015, 13:327-335

[81] Cao B, Liu N, Wang W. High glucose prevents osteogenic differentiation of mesenchymal stem cells via lncRNA AK028326/CXCL13 pathway. Biomed. Pharmacother., 2016, 84:544-551

[82] Miyoshi N et al. Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells, 2000, 5:211-220

[83] Zhuang W et al. Upregulation of lncRNA MEG3 promotes osteogenic differentiation of mesenchymal stem cells from multiple myeloma patients by targeting BMP4 transcription. Stem Cells, 2015, 33:1985-1997

[84] Bandyopadhyay A et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet., 2006, 2:e216

[85] Li Z et al. Long non-coding RNA MEG3 inhibits adipogenesis and promotes osteogenesis of human adipose-derived mesenchymal stem cells via miR-140-5p. Mol. Cell. Biochem., 2017, 433:51-60

[86] Huang Y, Zheng Y, Jia L, Li W. Long noncoding RNA H19 promotes osteoblast differentiation via TGF-β1/Smad3/HDAC signaling pathway by deriving miR-675. Stem Cells, 2015, 33:3481-3492

[87] Liang WC et al. H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous. RNA Sci. Rep., 2016, 6:20121

[88] Kang JS, Alliston T, Delston R, Derynck R. Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J., 2005, 24:2543-2555

[89] Wu J et al. Long non-coding RNA H19 mediates mechanical tension-induced osteogenesis of bone marrow mesenchymal stem cells via FAK by sponging miR-138. Bone, 2018, 108:62-70

[90] Tang S et al. LncRNA-OG promotes the osteogenic differentiation of bone marrow-derived mesenchymal stem cells under the regulation of hnRNPK. Stem Cells Dayt. Ohio, 2019, 37:270-283

[91] He Q et al. Long noncoding RNA TUG1 facilitates osteogenic differentiation of periodontal ligament stem cells via interacting with Lin28A. Cell Death Dis., 2018, 9

[92] Shang G et al. Long non-coding RNA TCONS_00041960 enhances osteogenesis and inhibits adipogenesis of rat bone marrow mesenchymal stem cell by targeting miR-204-5p and miR-125a-3p. J. Cell. Physiol., 2018, 233:6041-6051

[93] Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann. N. Y. Acad. Sci., 2002, 966:73-81

[94] Yuan, H. et al. A novel long noncoding RNA PGC1β-OT1 regulates adipocyte and osteoblast differentiation through antagonizing miR-148a-3p. Cell Death Differ. 1. https://doi.org/10.1038/s41418-019-0296-7 (2019).

[95] Feng L 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

[96] Gao Y et al. Long noncoding RNA MALAT1 promotes osterix expression to regulate osteogenic differentiation by targeting miRNA-143 in human bone marrow-derived mesenchymal stem cells. J. Cell. Biochem., 2018, 119:6986-6996

[97] Jiang XR et al. Long non-coding RNA HULC promotes proliferation and osteogenic differentiation of bone mesenchymal stem cells via down-regulation of miR-195. Eur. Rev. Med. Pharmacol. Sci., 2018, 22:2954-2965

[98] Almeida MI et al. miR-195 in human primary mesenchymal stromal/stem cells regulates proliferation, osteogenesis and paracrine effect on angiogenesis. Oncotarget, 2016, 7:7-22

[99] Wu R et al. Long non-coding RNA HIF1A-AS2 facilitates adipose-derived stem cells (ASCs) osteogenic differentiation through miR-665/IL6 axis via PI3K/Akt signaling pathway. Stem Cell Res. Ther., 2018, 9:348

[100] Xu Y, Wang S, Tang C, Chen W. Upregulation of long non-coding RNA HIF 1α-anti-sense 1 induced by transforming growth factor-β-mediated targeting of sirtuin 1 promotes osteoblastic differentiation of human bone marrow stromal cells. Mol. Med. Rep., 2015, 12:7233-7238

[101] Chen D et al. Comparison of HIF1A‑AS1 and HIF1A‑AS2 in regulating HIF‑1α and the osteogenic differentiation of PDLCs under hypoxia. Int. J. Mol. Med., 2017, 40:1529-1536

[102] Weng J, Peng W, Zhu S, Chen S. Long noncoding RNA Sponges miR-454 to promote osteogenic differentiation in maxillary sinus membrane stem cells. Implant Dent., 2017, 26:178-186

[103] Peng W et al. Lnc-NTF3-5 promotes osteogenic differentiation of maxillary sinus membrane stem cells via sponging miR-93-3p. Clin. Implant. Dent. Relat. Res., 2018, 20:110-121

[104] Gao X, Ge J, Li W, Zhou W, Xu L. LncRNA KCNQ1OT1 promotes osteogenic differentiation to relieve osteolysis via Wnt/β-catenin activation. Cell Biosci., 2018, 8:19

[105] Touaitahuata H, Blangy A, Vives V. Modulation of osteoclast differentiation and bone resorption by Rho GTPases. Small GTPases, 2014, 5:e28119

[106] Zhu, S. et al. From the clinical problem to the basic research-co-culture models of osteoblasts and osteoclasts. Int. J. Mol. Sci. 19, pii: E2284 (2018).

[107] Dou C et al. Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis. Sci. Rep., 2016, 6

[108] Hemingway F, Taylor R, Knowles HJ, Athanasou NA. RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF I and IGF II. Bone, 2011, 48:938-944

[109] Liu C et al. LncRNA AK077216 promotes RANKL-induced osteoclastogenesis and bone resorption via NFATc1 by inhibition of NIP45. J. Cell. Physiol., 2019, 234:1606-1617

[110] Kim, J.H., & Kim, N. Regulation of NFATc1 in Osteoclast Differentiation. J. Bone Metab. 21, 233–241 (2014).

[111] Grigoriadis AE et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science, 1994, 266:443-448

[112] Choe, J.-Y., Park, K.Y. & Kim S.-K. Monosodium Urate in the Presence of RANKL Promotes Osteoclast Formation through Activation of c-Jun N-Terminal Kinase. Mediators Inflamm. 2015:597512, 1–12 (2015)

[113] Quan H et al. LncRNA-AK131850 sponges MiR-93-5p in newborn and mature osteoclasts to enhance the secretion of vascular endothelial growth factor a promoting vasculogenesis of endothelial progenitor cells. Cell. Physiol. Biochem., 2018, 46:401-417

[114] Yang, C.-A. et al. lncRNA NTT/PBOV1 axis promotes monocyte differentiation and is elevated in rheumatoid arthritis. Int. J. Mol. Sci. 19, pii: E2806 (2018).

[115] Zhang X et al. A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster. Blood, 2009, 113:2526-2534

[116] Goltzman D. Functions of vitamin D in bone. Histochem. Cell Biol., 2018, 149:305-312

[117] Jiang YJ, Bikle DD. LncRNA profiling reveals new mechanism for VDR protection against skin cancer formation. J. Steroid Biochem. Mol. Biol., 2014, 144 Pt A:87-90

[118] Riege, K. et al. Massive effect on LncRNAs in human monocytes during fungal and bacterial infections and in response to vitamins A and D. Sci. Rep. 7: 40598 (2017).

[119] Chen S et al. H19 overexpression induces resistance to 1,25(OH)2D3 by targeting VDR through miR-675-5p in colon cancer cells. Neoplasia, 2017, 19:226-236

[120] Ström O et al. Osteoporosis: burden, health care provision and opportunities in the EU: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch. Osteoporos., 2011, 6:59-155

[121] Huang G et al. FGF2 and FAM201A affect the development of osteonecrosis of the femoral head after femoral neck fracture. Gene, 2018, 652:39-47

[122] Silva AM et al. Extracellular Vesicles: Immunomodulatory messengers in the context of tissue repair/regeneration. Eur. J. Pharm. Sci., 2017, 98:86-95

[123] Pearson MJ, Jones SW. Review: long noncoding rnas in the regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis. Arthritis Rheumatol., 2016, 68:2575-2583

[124] Tang Y, Zhou T, Yu X, Xue Z, Shen N. The role of long non-coding RNAs in rheumatic diseases. Nat. Rev. Rheumatol., 2017, 13:657-669

[125] Song J et al. PBMC and exosome-derived Hotair is a critical regulator and potent marker for rheumatoid arthritis. Clin. Exp. Med., 2015, 15:121-126

[126] Zhang HJ et al. LncRNA HOTAIR alleviates rheumatoid arthritis by targeting miR-138 and inactivating NF-κB pathway. Int. Immunopharmacol., 2017, 50:283-290

[127] Spurlock CF, Tossberg JT, Matlock BK, Olsen NJ, Aune TM. Methotrexate inhibits NF-κB activity via long intergenic (noncoding) RNA-p21 induction. Arthritis Rheumatol., 2014, 66:2947-2957

[128] Magagula L, Gagliardi M, Naidoo J, Mhlanga M. Lnc-ing inflammation to disease. Biochem. Soc. Trans., 2017, 45:953-962

[129] Pearson Mark J et al. Long intergenic noncoding rnas mediate the human chondrocyte inflammatory response and are differentially expressed in osteoarthritis cartilage. Arthritis Rheumatol., 2015, 68:845-856

[130] Wang L et al. Long noncoding RNA related to periodontitis interacts with miR-182 to upregulate osteogenic differentiation in periodontal mesenchymal stem cells of periodontitis patients. Cell Death Dis., 2016, 7

[131] Huang Z et al. Identification of differentially expressed long non-coding RNAs in polarized macrophages. Sci. Rep., 2016, 6

[132] Atianand MK et al. A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation. Cell, 2016, 165:1672-1685

[133] Bai Y, Lv Y, Wang W, Sun G, Zhang H. LncRNA NEAT1 promotes inflammatory response and induces corneal neovascularization. J. Mol. Endocrinol., 2018, 61:231-239

[134] Fiedler J et al. Development of long noncoding RNA-based strategies to modulate tissue vascularization. J. Am. Coll. Cardiol., 2015, 66:2005-2015

[135] Michalik KM et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ. Res., 2014, 114:1389-1397

[136] Li X et al. Long non-coding RNA MALAT1 promotes proliferation, angiogenesis, and immunosuppressive properties of mesenchymal stem cells by inducing VEGF and IDO. J. Cell. Biochem., 2017, 118:2780-2791

[137] Komori T. Animal models for osteoporosis. Eur. J. Pharmacol., 2015, 759:287-294

[138] Hao L, Fu J, Tian Y, Wu J. Systematic analysis of lncRNAs, miRNAs and mRNAs for the identification of biomarkers for osteoporosis in the mandible of ovariectomized mice. Int. J. Mol. Med., 2017, 40:689-702

[139] Feng X et al. Long non-coding RNA BDNF-AS modulates osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Mol. Cell. Biochem., 2018, 445:59-65

[140] Su YW et al. Roles of neurotrophins in skeletal tissue formation and healing. J. Cell. Physiol., 2018, 233:2133-2145

[141] Wang Q et al. LncRNA MEG3 inhibited osteogenic differentiation of bone marrow mesenchymal stem cells from postmenopausal osteoporosis by targeting miR-133a-3p. Biomed. Pharmacother., 2017, 89:1178-1186

[142] Chen S, Jia L, Zhang S, Zheng Y, Zhou Y. DEPTOR regulates osteogenic differentiation via inhibiting MEG3-mediated activation of BMP4 signaling and is involved in osteoporosis. Stem Cell Res. Ther., 2018, 9:185

[143] Wang Y, Luo TB, Liu L, Cui ZQ. LncRNA LINC00311 promotes the proliferation and differentiation of osteoclasts in osteoporotic rats through the notch signaling pathway by targeting DLL3. Cell. Physiol. Biochem., 2018, 47:2291-2306

[144] Li B et al. LncRNA-H19 modulates Wnt/β-catenin signaling by targeting Dkk4 in hindlimb unloaded rat. Orthop. Surg., 2017, 9:319-327

[145] Daskalakis NP, Provost AC, Hunter RG, Guffanti G. Noncoding RNAs: stress, glucocorticoids, and posttraumatic stress disorder. Biol. Psychiatry, 2018, 83:849-865

[146] He X et al. LncRNAs: key players and novel insights into diabetes mellitus. Oncotarget, 2017, 8:71325-71341

[147] Ren W, Yang X. Pathophysiology of long non-coding RNAs in ischemic stroke. Front. Mol. Neurosci., 2018, 11:96

[148] Laura IddaM, Rachel Munk, Kotb Abdelmohsen, Myriam Gorospe. Noncoding RNAs in Alzheimer’s disease. Wiley Interdiscip. Rev. RNA, 2018, 9:e1463

[149] Simion V, Haemmig S, Feinberg MW. LncRNAs in vascular biology and disease. Vascul. Pharmacol., 2018

[150] Bär C, Chatterjee S, Thum T. Long noncoding RNAs in cardiovascular pathology, diagnosis, and therapy. Circulation, 2016, 134:1484-1499

[151] Zhang TN et al. Non-coding RNA: a potential biomarker and therapeutic target for sepsis. Oncotarget, 2017, 8:91765-91778

[152] Tang Y, Zhou T, Yu X, Xue Z, Shen N. The role of long non-coding RNAs in rheumatic diseases. Nat. Rev. Rheumatol., 2017, 13:657-669

[153] Lin C, Yang L. Long noncoding RNA in cancer: wiring signaling circuitry. Trends Cell Biol., 2018, 28:287-301

[154] Fei Q et al. Identification of aberrantly expressed long non-coding RNAs in postmenopausal osteoporosis. Int. J. Mol. Med., 2018, 41:3537-3550

[155] Tong X, Gu P, Xu S, Lin X. Long non-coding RNA-DANCR in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis. Biosci. Biotechnol. Biochem., 2015, 79:732-737

[156] Zeng Q et al. Genome-wide association study of lncRNA polymorphisms with bone mineral density. Ann. Hum. Genet., 2018

[157] Kotani M et al. Systemic circulation and bone recruitment of osteoclast precursors tracked by using fluorescent imaging techniques. J. Immunol., 2013, 190:605-612

[158] Daswani B, Khatkhatay MI. ‘Omics’ signatures in peripheral monocytes from women with low BMD condition. J. Osteoporos., 2018, 2018:8726456

[159] Zha L et al. TNF-α contributes to postmenopausal osteoporosis by synergistically promoting RANKL-induced osteoclast formation. Biomed. Pharmacother., 2018, 102:369-374

[160] Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev., 2000, 21:115-137

[161] Schlosser, K. et al. Assessment of circulating LncRNAs under physiologic and pathologic conditions in humans reveals potential limitations as biomarkers. Sci. Rep. 6: 36596 (2016).

[162] Silva A, Bullock M, Calin G. The clinical relevance of long non-coding RNAs in cancer. Cancers, 2015, 7:2169-2182

[163] Styrkarsdottir U et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med., 2008, 358:2355-2365

[164] Chen XF et al. An osteoporosis risk SNP at 1p36.12 acts as an allele-specific enhancer to modulate LINC00339 expression via long-range loop formation. Am. J. Hum. Genet., 2018, 102:776-793

[165] Strzelecka-Kiliszek A et al. Functions of Rho family of small GTPases and Rho-associated coiled-coil kinases in bone cells during differentiation and mineralization. Biochim. Biophys. Acta, 2017, 1861:1009-1023

[166] Zheng HF et al. Whole‐genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature, 2015, 526:112

[167] List Results of ClinicalTrials.gov for long non-coding RNA. https://clinicaltrials.gov/ct2/results?term=long+non-coding+RNA. Accessed May 13, 2018.

[168] Betz, V. M. et al. Recent advances in gene-enhanced bone tissue engineering. J. Gene Med. 20, e3018 (2018).

[169] Sidi AA et al. Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette–Guerin. J. Urol., 2008, 180:2379-2383

[170] Chen CL et al. Suppression of hepatocellular carcinoma by baculovirus-mediated expression of long non-coding RNA PTENP1 and microRNA regulation. Biomaterials, 2015, 44:71-81

[171] Chang L et al. Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma. Oncotarget, 2016, 7:23988-24004

[172] Malek E, Jagannathan S, Driscoll JJ. Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer. Oncotarget, 2014, 5:8027-8038

[173] Wang R et al. Preclinical study using Malat1 small interfering RNA or androgen receptor splicing variant 7 degradation enhancer ASC-J9® to suppress enzalutamide-resistant prostate cancer progression. Eur. Urol., 2017, 72:835-844

[174] Hu, Y. et al. Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia. https://doi.org/10.1038/s41375-018-0104-2 (2018)

[175] Jiang Y et al. Downregulation of long non-coding RNA Kcnq1ot1: an important mechanism of arsenic trioxide-induced long QT syndrome. Cell. Physiol. Biochem., 2018, 45:192-202

[176] Lennox KA, Behlke MA. Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides. Nucleic Acids Res., 2016, 44:863-877

[177] Vickers TA et al. Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J. Biol. Chem., 2003, 278:7108-7118

[178] Liu, F. et al. Current transport systems and clinical applications for small interfering RNA (siRNA) drugs. Mol. Diagn. Ther. 22, 551–569 (2018).

[179] Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell. Metab., 2018, 27:714-739

[180] Moore CB, Guthrie EH, Huang MTH, Taxman DJ. Short hairpin RNA (shRNA): design, delivery, and assessment of gene knockdown. Methods Mol. Biol., 2010, 629:141-158

[181] Rao DD, Senzer N, Cleary MA, Nemunaitis J. Comparative assessment of siRNA and shRNA off target effects: what is slowing clinical development. Cancer Gene. Ther., 2009, 16:807-809

[182] Ma P et al. Extracellular vesicles-mediated noncoding RNAs transfer in cancer. J. Hematol. Oncol., 2017, 10:57

[183] Teixeira JH, Silva AM, Almeida MI, Barbosa MA, Santos SG. Circulating extracellular vesicles: their role in tissue repair and regeneration. Transfus. Apher. Sci., 2016, 55:53-61

[184] Zhang J et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res. Ther., 2016, 7:136

[185] Martins M, Ribeiro D, Martins A, Reis RL, Neves NM. Extracellular vesicles derived from osteogenically induced human bone marrow mesenchymal stem cells can modulate lineage commitment. Stem Cell Rep., 2016, 6:284-291

[186] Ekström K et al. Monocyte exosomes stimulate the osteogenic gene expression of mesenchymal stem cells. PLoS One, 2013, 8:e75227

[187] Inder, K. L. et al. Cavin-1/PTRF alters prostate cancer cell-derived extracellular vesicle content and internalization to attenuate extracellular vesicle-mediated osteoclastogenesis and osteoblast proliferation. J. Extracell. Vesicles 3: 23784 (2014).

[188] Xie Y et al. Involvement of serum-derived exosomes of elderly patients with bone loss in failure of bone remodeling via alteration of exosomal bone-related proteins. Aging Cell., 2018, 17:e12758

[189] Davidovich C, Cech TR. The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2. RNA, 2015, 21:2007-2022

[190] Lee S et al. Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins. Cell, 2016, 164:69-80

[191] Adams BD, Parsons C, Walker L, Zhang WC, Slack FJ. Targeting noncoding RNAs in disease. J. Clin. Invest., 2017, 127:761-771

[192] Liu, Y. et al. Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites. Nat. Biotechnol. 36, 1203–1210  (2018).

[193] Baliou S et al. CRISPR therapeutic tools for complex genetic disorders and cancer (Review). Int. J. Oncol., 2018, 53:443-468

[194] Ballarino, M. et al. Deficiency in the nuclear long noncoding RNA Charme causes myogenic defects and heart remodeling in mice. EMBO J. 37, e99697 (2018).

[195] Goyal A et al. Challenges of CRISPR/Cas9 applications for long non-coding RNA genes. Nucleic Acids Res., 2017, 45:e12

[196] Yan Y et al. Elevated RNA expression of long non‑coding HOTAIR promotes cell proliferation and predicts a poor prognosis in patients with diffuse large B cell lymphoma. Mol. Med. Rep., 2016, 13:5125-5131

[197] Zhang J et al. Overexpression of long non-coding RNA colon cancer-associated transcript 2 is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. Oncol. Lett., 2017, 14:6907-6914

[198] Ozawa T et al. CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 ‘gene desert’, serve as important prognostic biomarkers in colorectal cancer. Ann. Oncol., 2017, 28:1882-1888

[199] Tontonoz P et al. Long noncoding RNA facilitated gene therapy reduces atherosclerosis in a murine model of familial hypercholesterolemia. Circulation, 2017, 136:776-778

Funding

Fundação para a Ciência e a Tecnologia - FCT (POCI-01-0145-FEDER-031402)

FCT - Fundação para a Ciência e a Tecnologia