Distinct Subsets of Noncoding RNAs Are Strongly Associated With BMD and Fracture, Studied in Weight-Bearing and Non-Weight-Bearing Human Bone.
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
26
07
2019
revised:
22
01
2020
accepted:
26
01
2020
pubmed:
6
2
2020
medline:
29
7
2021
entrez:
5
2
2020
Statut:
ppublish
Résumé
We investigated mechanisms resulting in low bone mineral density (BMD) and susceptibility to fracture by comparing noncoding RNAs (ncRNAs) in biopsies of non-weight-bearing (NWB) iliac (n = 84) and weight bearing (WB) femoral (n = 18) postmenopausal bone across BMDs varying from normal (T-score > -1.0) to osteoporotic (T-score ≤ -2.5). Global bone ncRNA concentrations were determined by PCR and microchip analyses. Association with BMD or fracture, adjusted by age and body mass index, were calculated using linear and logistic regression and least absolute shrinkage and selection operator (Lasso) analysis. At 10% false discovery rate (FDR), 75 iliac bone ncRNAs and 94 femoral bone ncRNAs were associated with total hip BMD. Eight of the ncRNAs were common for the two sites, but five of them (miR-484, miR-328-3p, miR-27a-5p, miR-28-3p, and miR-409-3p) correlated positively to BMD in femoral bone, but negatively in iliac bone. Of predicted pathways recognized in bone metabolism, ECM-receptor interaction and proteoglycans in cancer emerged at both sites, whereas fatty acid metabolism and focal adhesion were only identified in iliac bone. Lasso analysis and cross-validations identified sets of nine bone ncRNAs correlating strongly with adjusted total hip BMD in both femoral and iliac bone. Twenty-eight iliac ncRNAs were associated with risk of fracture (FDR < 0.1). The small nucleolar RNAs, RNU44 and RNU48, have a function in stabilization of ribosomal RNAs (rRNAs), and their association with fracture and BMD suggest that aberrant processing of rRNAs may be involved in development of osteoporosis. Cis-eQTL (expressed quantitative trait loci) analysis of the iliac bone biopsies identified two loci associated with microRNAs (miRNAs), one previously identified in a heel-BMD genomewide association study (GWAS). In this comprehensive investigation of the skeletal genetic background in postmenopausal women, we identified functional bone ncRNAs associated to fracture and BMD, representing distinct subsets in WB and NWB skeletal sites. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Substances chimiques
RNA, Untranslated
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1065-1076Informations de copyright
© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Références
Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med. 1997;103(2A):12S-7S.
Magaziner J, Lydick E, Hawkes W, et al. Excess mortality attributable to hip fracture in white women aged 70 years and older. Am J Public Health. 1997;87(10):1630-6.
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22(3):465-75.
Jian WX, Long JR, Li MX, Liu XH, Deng HW. Genetic determination of variation and covariation of bone mineral density at the hip and spine in a Chinese population. J Bone Miner Metab. 2005;23(2):181-5.
Sigurdsson G, Halldorsson BV, Styrkarsdottir U, Kristjansson K, Stefansson K. Impact of genetics on low bone mass in adults. J Bone Miner Res. 2008;23(10):1584-90.
Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S. Genetic determinants of bone mass in adults. A twin study. J Clin Invest. 1987;80(3):706-10.
Dequeker J, Nijs J, Verstraeten A, Geusens P, Gevers G. Genetic determinants of bone mineral content at the spine and radius: a twin study. Bone. 1987;8(4):207-9.
Morris JA, Kemp JP, Youlten SE, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019;51(2):258-66.
Lien TG, Borgan O, Reppe S, Gautvik K, Glad IK. Integrated analysis of DNA-methylation and gene expression using high-dimensional penalized regression: a cohort study on bone mineral density in postmenopausal women. BMC Med Genomics. 2018;11(1):24.
Reppe S, Lien TG, Hsu YH, et al. Distinct DNA methylation profiles in bone and blood of osteoporotic and healthy postmenopausal women. Epigenetics. 2017;12(8):674-87.
Reppe S, Refvem H, Gautvik VT, et al. Eight genes are highly associated with BMD variation in postmenopausal Caucasian women. Bone. 2010;46(3):604-12.
Geeleher P, Huang SR, Gamazon ER, Golden A, Seoighe C. The regulatory effect of miRNAs is a heritable genetic trait in humans. BMC Genomics. 2012;13:383.
Liebers R, Rassoulzadegan M, Lyko F. Epigenetic regulation by heritable RNA. PLoS Genet. 2014;10(4):e1004296.
Ying SY, Chang DC, Lin SL. The microRNA (miRNA): overview of the RNA genes that modulate gene function. Mol Biotechnol. 2008;38(3):257-68.
Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42(D1):D68-73.
Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 2014;157(1):77-94.
Watkins NJ, Bohnsack MT. The box C/D and H/ACA snoRNPs: Key players in the modification, processing and the dynamic folding of ribosomal RNA. WIREs RNA. 2012;3(3):397-414.
Steitz JA, Tycowski KT. Small RNA chaperones for ribosome biogenesis. Science. 1995;270(5242):1626-7.
Kalogeropoulos M, Varanasi SS, Olstad OK, et al. Zic1 transcription factor in bone: neural developmental protein regulates mechanotransduction in osteocytes. FASEB J. 2010;24(8):2893-903.
Varanasi SS, Olstad OK, Swan DC, et al. Skeletal site-related variation in human trabecular bone transcriptome and signaling. PLoS One. 2010;5(5):e10692.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57:289-300.
Efron B, Hastie T, Johnstone I, Tibshirani R. Least angle regression. Ann Stat. 2004;32(2):407-51.
Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33(1):1-22.
Vlachos IS, Zagganas K, Paraskevopoulou MD, et al. DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Res. 2015;43(W1):W460-6.
Alexiou P, Maragkakis M, Papadopoulos GL, Reczko M, Hatzigeorgiou AG. Lost in translation: an assessment and perspective for computational microRNA target identification. Bioinformatics. 2009;25(23):3049-55.
Nielson CM, Liu CT, Smith AV, et al. Novel genetic variants associated with increased vertebral volumetric BMD, reduced vertebral fracture risk, and increased expression of SLC1A3 and EPHB2. J Bone Miner Res. 2016;31(12):2085-97.
Zhan XW, Hu YN, Li BS, Abecasis GR, Liu DJJ. RVTESTS: an efficient and comprehensive tool for rare variant association analysis using sequence data. Bioinformatics. 2016;32(9):1423-6.
De-Ugarte L, Yoskovitz G, Balcells S, et al. MiRNA profiling of whole trabecular bone: identification of osteoporosis-related changes in miRNAs in human hip bones. BMC Med Genomics. 2015;8:75.
Tibshirani R. Regression shrinkage and selection via the Lasso. J R Stat Soc Series B Stat Methodol. 1996;58(1):267-88.
Li Z, Sillanpaa MJ. Overview of LASSO-related penalized regression methods for quantitative trait mapping and genomic selection. Theor Appl Genet. 2012;125(3):419-35.
Hsu YH, Estrada K, Evangelou E, et al. Meta-analysis of genomewide association studies reveals genetic variants for hip bone geometry. J Bone Miner Res. 2019;34(7):1284-96.
Chen J, Long F. mTOR signaling in skeletal development and disease. Bone Res. 2018;6:1.
Shi Y, He G, Lee WC, McKenzie JA, Silva MJ, Long F. Gli1 identifies osteogenic progenitors for bone formation and fracture repair. Nat Commun. 2017;8(1):2043.
Fan JB, Liu W, Zhu XH, et al. EGFR-AKT-mTOR activation mediates epiregulin-induced pleiotropic functions in cultured osteoblasts. Mol Cell Biochem. 2015;398(1-2):105-13.
Manolagas SC. Wnt signaling and osteoporosis. Maturitas. 2014;78(3):233-7.
Paccou J, Penel G, Chauveau C, Cortet B, Hardouin P. Marrow adiposity and bone: Review of clinical implications. Bone. 2019;118:8-15.
Hawkes CP, Mostoufi-Moab S. Fat-bone interaction within the bone marrow milieu: impact on hematopoiesis and systemic energy metabolism. Bone. 2019;119:57-64.
Xiang L, Yu H, Zhang X, et al. The versatile hippo pathway in oral-maxillofacial development and bone remodeling. Dev Biol. 2018;440(2):53-63.
Lin Z, Tang Y, Tan H, Cai D. MicroRNA-92a-1-5p influences osteogenic differentiation of MC3T3-E1 cells by regulating beta-catenin. J Bone Miner Metab. 2019;37(2):264-72.
Penzkofer D, Bonauer A, Fischer A, et al. Phenotypic characterization of miR-92a−/− mice reveals an important function of miR-92a in skeletal development. PLoS One. 2014;9(6):e101153.
Murata K, Ito H, Yoshitomi H, et al. Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice. J Bone Miner Res. 2014;29(2):316-26.
Ahn TK, Kim JO, Kumar H, et al. Polymorphisms of miR-146a, miR-149, miR-196a2, and miR-499 are associated with osteoporotic vertebral compression fractures in Korean postmenopausal women. J Orthop Res. 2018;36(1):244-53.
Kiss-Laszlo Z, Henry Y, Bachellerie JP, Caizergues-Ferrer M, Kiss T. Site-specific ribose methylation of preribosomal RNA: A novel function for small nucleolar RNAs. Cell. 1996;85(7):1077-88.
Lestrade L, Weber MJ. snoRNA-LBME-db, a comprehensive database of human H/ACA and C/D box snoRNAs. Nucleic Acids Res. 2006;34(Database issue):D158-62.
Huttenhofer A, Kiefmann M, Meier-Ewert S, et al. RNomics: an experimental approach that identifies 201 candidates for novel, small, non-messenger RNAs in mouse. EMBO J. 2001;20(11):2943-53.
Sergiev PV, Aleksashin NA, Chugunova AA, Polikanov YS, Dontsova OA. Structural and evolutionary insights into ribosomal RNA methylation. Nat Chem Biol. 2018;14(3):226-35.
Ali SA, Zaidi SK, Dobson JR, et al. Transcriptional corepressor TLE1 functions with Runx2 in epigenetic repression of ribosomal RNA genes. Proc Natl Acad Sci U S A. 2010;107(9):4165-9.
Young DW, Hassan MQ, Pratap J, et al. Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2. Nature. 2007;445(7126):442-6.
Ali SA, Zaidi SK, Dacwag CS, et al. Phenotypic transcription factors epigenetically mediate cell growth control. Proc Natl Acad Sci U S A. 2008;105(18):6632-7.
Parker MS, Balasubramaniam A, Parker SL. The expansion segments of human 28S rRNA match microRNAs much above 18S rRNA or core segments. Microrna. 2018;7(2):128-37.
Verbeeren J, Niemela EH, Turunen JJ, et al. An ancient mechanism for splicing control: U11 snRNP as an activator of alternative splicing. Mol Cell. 2010;37(6):821-33.
Dupuis-Sandoval F, Poirier M, Scott MS. The emerging landscape of small nucleolar RNAs in cell biology. Wiley Interdiscip Rev RNA. 2015;6(4):381-97.
Dieci G, Preti M, Montanini B. Eukaryotic snoRNAs: a paradigm for gene expression flexibility. Genomics. 2009;94(2):83-8.
Kishore S, Gruber AR, Jedlinski DJ, Syed AP, Jorjani H, Zavolan M. Insights into snoRNA biogenesis and processing from PAR-CLIP of snoRNA core proteins and small RNA sequencing. Genome Biol. 2013;14(5):R45.
Weilner S, Skalicky S, Salzer B, et al. Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation. Bone. 2015;79:43-51.
Choi YJ, Jeong S, Yoon KA, et al. Deficiency of DGCR8 increases bone formation through downregulation of miR-22 expression. Bone. 2017;103:287-94.
Liang WC, Fu WM, Wang YB, et al. H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA. Sci Rep. 2016;6:20121.
Manochantr S, Marupanthorn K, Tantrawatpan C, Kheolamai P, Tantikanlayaporn D, Sanguanjit P. The effects of BMP-2, miR-31, miR-106a, and miR-148a on osteogenic differentiation of MSCs derived from amnion in comparison with MSCs derived from the bone marrow. Stem Cells Int. 2017;2017:7257628.
Yavropoulou MP, Anastasilakis AD, Makras P, Tsalikakis DG, Grammatiki M, Yovos JG. Expression of microRNAs that regulate bone turnover in the serum of postmenopausal women with low bone mass and vertebral fractures. Eur J Endocrinol. 2017;176(2):169-76.
Wang XN, Zhang LH, Cui XD, Wang MX, Zhang GY, Yu PL. lncRNA HOXA11-AS is involved in fracture healing through regulating mir-124-3p. Eur Rev Med Pharmacol Sci. 2017;21(21):4771-6.
Qadir AS, Um S, Lee H, et al. miR-124 negatively regulates osteogenic differentiation and in vivo bone formation of mesenchymal stem cells. J Cell Biochem. 2015;116(5):730-42.
Zhao N, Han D, Liu Y, et al. DLX3 negatively regulates osteoclastic differentiation through microRNA-124. Exp Cell Res. 2016;341(2):166-76.
Chen L, Holmstrom K, Qiu W, et al. MicroRNA-34a inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells. Stem Cells. 2014;32(4):902-12.
Hupkes M, Sotoca AM, Hendriks JM, van Zoelen EJ, Dechering KJ. MicroRNA miR-378 promotes BMP2-induced osteogenic differentiation of mesenchymal progenitor cells. BMC Mol Biol. 2014;15(1):1-15.
Kahai S, Lee SC, Lee DY, et al. MicroRNA miR-378 regulates nephronectin expression modulating osteoblast differentiation by targeting GalNT-7. PLoS One. 2009;4(10):e7535.
You L, Gu W, Chen L, Pan L, Chen J, Peng Y. MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway. Int J Clin Exp Pathol. 2014;7(10):7249-61.
Zeng HC, Bae Y, Dawson BC, et al. MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-beta signalling in osteoblasts. Nat Commun. 2017;8:15000.
Gu C, Xu Y, Zhang S, et al. miR-27a attenuates adipogenesis and promotes osteogenesis in steroid-induced rat BMSCs by targeting PPARgamma and GREM1. Sci Rep. 2016;6:38491.
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(1):253-65.
Gong Y, Lu J, Yu X, Yu Y. Expression of Sp7 in Satb2-induced osteogenic differentiation of mouse bone marrow stromal cells is regulated by microRNA-27a. Mol Cell Biochem. 2016;417(1-2):7-16.
Van Metre TE Jr, Marsh DG, Adkinson NF Jr, et al. Immunotherapy for cat asthma. J Allergy Clin Immunol. 1988;82(6):1055-68.
Huang M, Qing Y, Shi Q, Cao Y, Song K. miR-342-3p elevates osteogenic differentiation of umbilical cord mesenchymal stem cells via inhibiting Sufu in vitro. Biochem Biophys Res Commun. 2017;491(3):571-7.
Guo Y, Tang CY, Man XF, et al. Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Ialpha2 expression via miR-342. FASEB J. 2016;30(12):4214-26.
Vimalraj S, Partridge NC, Selvamurugan N. A positive role of microRNA-15b on regulation of osteoblast differentiation. J Cell Physiol. 2014;229(9):1236-44.
Gao J, Yang T, Han J, et al. MicroRNA expression during osteogenic differentiation of human multipotent mesenchymal stromal cells from bone marrow. J Cell Biochem. 2011;112(7):1844-56.
Xu C, Zhang H, Gu W, et al. The microRNA-10a/ID3/RUNX2 axis modulates the development of ossification of posterior longitudinal ligament. Sci Rep. 2018;8(1):9225.
Deng L, Hu G, Jin L, Wang C, Niu H. Involvement of microRNA-23b in TNF-alpha-reduced BMSC osteogenic differentiation via targeting runx2. J Bone Miner Metab. 2018;36(6):648-60.
Waki T, Lee SY, Niikura T, et al. Profiling microRNA expression during fracture healing. BMC Musculoskelet Disord. 2016;17:83.
Bhushan R, Grunhagen J, Becker J, Robinson PN, Ott CE, Knaus P. miR-181a promotes osteoblastic differentiation through repression of TGF-beta signaling molecules. Int J Biochem Cell Biol. 2013;45(3):696-705.
Okamoto H, Matsumi Y, Hoshikawa Y, Takubo K, Ryoke K, Shiota G. Involvement of microRNAs in regulation of osteoblastic differentiation in mouse induced pluripotent stem cells. PLoS One. 2012;7(8):e43800.
Reppe S, Noer A, Grimholt RM, et al. Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. J Bone Miner Res. 2015;30(2):249-56.
Lee EJ, Kim SM, Choi B, et al. Interleukin-32 gamma stimulates bone formation by increasing miR-29a in osteoblastic cells and prevents the development of osteoporosis. Sci Rep. 2017;7:40240.
Kapinas K, Kessler CB, Delany AM. miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling. J Cell Biochem. 2009;108(1):216-24.
Ko JY, Chuang PC, Ke HJ, Chen YS, Sun YC, Wang FS. MicroRNA-29a mitigates glucocorticoid induction of bone loss and fatty marrow by rescuing Runx2 acetylation. Bone. 2015;81:80-8.
Roberto VP, Tiago DM, Silva IA, Cancela ML. MiR-29a is an enhancer of mineral deposition in bone-derived systems. Arch Biochem Biophys. 2014;564:173-83.
Kapinas K, Kessler C, Ricks T, Gronowicz G, Delany AM. miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. J Biol Chem. 2010;285(33):25221-31.
Dernowsek JA, Pereira MC, Fornari TA, et al. Posttranscriptional interaction between miR-450a-5p and miR-28-5p and STAT1 mRNA triggers osteoblastic differentiation of human mesenchymal stem cells. J Cell Biochem. 2017;118(11):4045-62.
Zhang L, Tang Y, Zhu X, et al. Overexpression of MiR-335-5p promotes bone formation and regeneration in mice. J Bone Miner Res. 2017;32(12):2466-75.
Jeong BC, Kang IH, Hwang YC, Kim SH, Koh JT. MicroRNA-194 reciprocally stimulates osteogenesis and inhibits adipogenesis via regulating COUP-TFII expression. Cell Death Dis. 2014;5:e1532.
Huang X, Li D, Wang Z, et al. Study of microRNAs targeted Dvl2 on the osteoblasts differentiation of rat BMSCs in hyperlipidemia environment. J Cell Physiol. 2018;233(9):6758-66.
Seeliger C, Karpinski K, Haug AT, et al. Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J Bone Miner Res. 2014;29(8):1718-28.
Garmilla-Ezquerra P, Sanudo C, Delgado-Calle J, Perez-Nunez MI, Sumillera M, Riancho JA. Analysis of the bone microRNome in osteoporotic fractures. Calcif Tissue Int. 2015;96(1):30-7.
Zeng Q, Wang Y, Gao J, et al. miR-29b-3p regulated osteoblast differentiation via regulating IGF-1 secretion of mechanically stimulated osteocytes. Cell Mol Biol Lett. 2019;24:11.
Oshima G, Poli EC, Bolt MJ, et al. DNA methylation controls metastasis-suppressive 14q32-encoded miRNAs. Cancer Res. 2019;79(3):650-62.
Huang H, Zhang C, Wang B, et al. Transduction with lentiviral vectors altered the expression profile of host microRNAs. J Virol. 2018;92(18):e00503-18.
Jung DE, Park SB, Kim K, Kim C, Song SY. CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway. Sci Rep. 2017;7(1):10921.