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Published in: Journal of Bone and Mineral Metabolism 3/2017

01-05-2017 | Original Article

MiR-142-5p promotes bone repair by maintaining osteoblast activity

Authors: Manli Tu, Juanjuan Tang, Hongbo He, Peng Cheng, Chao Chen

Published in: Journal of Bone and Mineral Metabolism | Issue 3/2017

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Abstract

MicroRNAs play important roles in regulating bone regeneration and remodeling. However, the pathophysiological roles of microRNAs in bone repair remain unclear. Here we identify a significant upregulation of miR-142-5p correlated with active osteoblastogenesis during the bone healing process. In vitro, miR-142-5p promoted osteoblast activity and matrix mineralization by targeting the gene encoding WW-domain-containing E3 ubiquitin protein ligase 1. We also found that the expression of miR-142-5p in the callus of aged mice was lower than that in the callus of young mice and directly correlated with the age-related delay in bone healing. Furthermore, treatment with agomir-142-5p in the fracture areas stimulated osteoblast activity which repaired the bone fractures in aged mice. Thus, our study revealed that miR-142-5p plays a crucial role in healing fractures by maintaining osteoblast activity, and provided a new molecular target therapeutic strategy for bone healing.
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Literature
2.
go back to reference Chrischilles EA, Butler CD, Davis CS, Wallace RB (1991) A model of lifetime osteoporosis impact. Arch Intern Med 151:2026–2032CrossRefPubMed Chrischilles EA, Butler CD, Davis CS, Wallace RB (1991) A model of lifetime osteoporosis impact. Arch Intern Med 151:2026–2032CrossRefPubMed
3.
go back to reference Riggs BL, Melton LJ 3rd (1995) The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17:505S–511SCrossRefPubMed Riggs BL, Melton LJ 3rd (1995) The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17:505S–511SCrossRefPubMed
4.
go back to reference Nelson FR, Brighton CT, Ryaby J, Simon BJ, Nielson JH, Lorich DG, Bolander M, Seelig J (2003) Use of physical forces in bone healing. J Am Acad Orthop Surg 11:344–354CrossRefPubMed Nelson FR, Brighton CT, Ryaby J, Simon BJ, Nielson JH, Lorich DG, Bolander M, Seelig J (2003) Use of physical forces in bone healing. J Am Acad Orthop Surg 11:344–354CrossRefPubMed
5.
go back to reference Rozen N, Lewinson D, Bick T, Meretyk S, Soudry M (2007) Role of bone regeneration and turnover modulators in control of fracture. Crit Rev Eukaryot Gene Expr 17:197–213CrossRefPubMed Rozen N, Lewinson D, Bick T, Meretyk S, Soudry M (2007) Role of bone regeneration and turnover modulators in control of fracture. Crit Rev Eukaryot Gene Expr 17:197–213CrossRefPubMed
6.
go back to reference Mehta M, Strube P, Peters A, Perka C, Hutmacher D, Fratzl P, Duda GN (2010) Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing: is osteoclast activity the key to age-related impaired healing? Bone 47:219–228CrossRefPubMed Mehta M, Strube P, Peters A, Perka C, Hutmacher D, Fratzl P, Duda GN (2010) Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing: is osteoclast activity the key to age-related impaired healing? Bone 47:219–228CrossRefPubMed
7.
go back to reference Claes L, Recknagel S, Ignatius A (2012) Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol 8:133–143CrossRefPubMed Claes L, Recknagel S, Ignatius A (2012) Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol 8:133–143CrossRefPubMed
8.
go back to reference Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118CrossRefPubMedPubMedCentral Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118CrossRefPubMedPubMedCentral
9.
go back to reference Nilsson BE, Edwards P (1969) Age and fracture healing: a statistical analysis of 418 cases of tibial shaft fractures. Geriatrics 24:112–117PubMed Nilsson BE, Edwards P (1969) Age and fracture healing: a statistical analysis of 418 cases of tibial shaft fractures. Geriatrics 24:112–117PubMed
10.
go back to reference Ekeland A, Engesoeter LB, Langeland N (1982) Influence of age on mechanical properties of healing fractures and intact bones in rats. Acta Orthop Scand 53:527–534CrossRefPubMed Ekeland A, Engesoeter LB, Langeland N (1982) Influence of age on mechanical properties of healing fractures and intact bones in rats. Acta Orthop Scand 53:527–534CrossRefPubMed
11.
go back to reference Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM (2001) Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 19:428–435CrossRefPubMed Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM (2001) Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 19:428–435CrossRefPubMed
12.
go back to reference Naik AA, Xie C, Zuscik MJ, Kingsley P, Schwarz EM, Awad H, Guldberg R, Drissi H, Puzas JE, Boyce B et al (2009) Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res 24:251–264CrossRefPubMed Naik AA, Xie C, Zuscik MJ, Kingsley P, Schwarz EM, Awad H, Guldberg R, Drissi H, Puzas JE, Boyce B et al (2009) Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res 24:251–264CrossRefPubMed
13.
go back to reference Meyer RA, Meyer MH, Phieffer LS, Banks DM (2001) Delayed union of femoral fractures in older rats: decreased gene expression. BMC Musculoskelet Disord 2:2CrossRefPubMedPubMedCentral Meyer RA, Meyer MH, Phieffer LS, Banks DM (2001) Delayed union of femoral fractures in older rats: decreased gene expression. BMC Musculoskelet Disord 2:2CrossRefPubMedPubMedCentral
15.
go back to reference Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S, Iwasaki M, Sunamura S, Takeuchi Y, Fukumoto S et al (2009) A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A 106:20794–20799CrossRefPubMedPubMedCentral Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S, Iwasaki M, Sunamura S, Takeuchi Y, Fukumoto S et al (2009) A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A 106:20794–20799CrossRefPubMedPubMedCentral
16.
go back to reference Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB, Stein GS (2008) A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A 105:13906–13911CrossRefPubMedPubMedCentral Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB, Stein GS (2008) A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A 105:13906–13911CrossRefPubMedPubMedCentral
17.
go back to reference Kobayashi T, Lu J, Cobb BS, Rodda SJ, McMahon AP, Schipani E, Merkenschlager M, Kronenberg HM (2008) Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci U S A 105:1949–1954CrossRefPubMedPubMedCentral Kobayashi T, Lu J, Cobb BS, Rodda SJ, McMahon AP, Schipani E, Merkenschlager M, Kronenberg HM (2008) Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci U S A 105:1949–1954CrossRefPubMedPubMedCentral
18.
go back to reference Wei J, Shi Y, Zheng L, Zhou B, Inose H, Wang J, Guo XE, Grosschedl R, Karsenty G (2012) miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J Cell Biol 197:509–521CrossRefPubMedPubMedCentral Wei J, Shi Y, Zheng L, Zhou B, Inose H, Wang J, Guo XE, Grosschedl R, Karsenty G (2012) miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J Cell Biol 197:509–521CrossRefPubMedPubMedCentral
19.
go back to reference Hu R, Liu W, Li H, Yang L, Chen C, Xia ZY, Guo LJ, Xie H, Zhou HD, Wu XP et al (2011) A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem 286:12328–12339CrossRefPubMedPubMedCentral Hu R, Liu W, Li H, Yang L, Chen C, Xia ZY, Guo LJ, Xie H, Zhou HD, Wu XP et al (2011) A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem 286:12328–12339CrossRefPubMedPubMedCentral
20.
go back to reference Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP et al (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677CrossRefPubMedPubMedCentral Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP et al (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677CrossRefPubMedPubMedCentral
21.
go back to reference Wang X, Guo B, Li Q, Peng J, Yang Z, Wang A, Li D, Hou Z, Lv K, Kan G et al (2013) miR-214 targets ATF4 to inhibit bone formation. Nat Med 19:93–100CrossRefPubMed Wang X, Guo B, Li Q, Peng J, Yang Z, Wang A, Li D, Hou Z, Lv K, Kan G et al (2013) miR-214 targets ATF4 to inhibit bone formation. Nat Med 19:93–100CrossRefPubMed
22.
go back to reference Murata K, Ito H, Yoshitomi H, Yamamoto K, Fukuda A, Yoshikawa J, Furu M, Ishikawa M, Shibuya H, Matsuda S (2014) Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice. J Bone Miner Res 29:316–326CrossRefPubMed Murata K, Ito H, Yoshitomi H, Yamamoto K, Fukuda A, Yoshikawa J, Furu M, Ishikawa M, Shibuya H, Matsuda S (2014) Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice. J Bone Miner Res 29:316–326CrossRefPubMed
23.
go back to reference Zhang X, Yan Z, Zhang J, Gong L, Li W, Cui J, Liu Y, Gao Z, Li J, Shen L et al (2011) Combination of hsa-miR-375 and hsa-miR-142-5p as a predictor for recurrence risk in gastric cancer patients following surgical resection. Ann Oncol 22:2257–2266CrossRefPubMed Zhang X, Yan Z, Zhang J, Gong L, Li W, Cui J, Liu Y, Gao Z, Li J, Shen L et al (2011) Combination of hsa-miR-375 and hsa-miR-142-5p as a predictor for recurrence risk in gastric cancer patients following surgical resection. Ann Oncol 22:2257–2266CrossRefPubMed
24.
go back to reference Schaefer JS, Montufar-Solis D, Vigneswaran N, Klein JR (2011) Selective upregulation of microRNA expression in peripheral blood leukocytes in IL-10−/− mice precedes expression in the colon. J Immunol 187:5834–5841CrossRefPubMedPubMedCentral Schaefer JS, Montufar-Solis D, Vigneswaran N, Klein JR (2011) Selective upregulation of microRNA expression in peripheral blood leukocytes in IL-10−/− mice precedes expression in the colon. J Immunol 187:5834–5841CrossRefPubMedPubMedCentral
25.
go back to reference Chaudhuri AD, Yelamanchili SV, Marcondes MC, Fox HS (2013) Up-regulation of microRNA-142 in simian immunodeficiency virus encephalitis leads to repression of sirtuin1. FASEB J 27:3720–3729CrossRefPubMedPubMedCentral Chaudhuri AD, Yelamanchili SV, Marcondes MC, Fox HS (2013) Up-regulation of microRNA-142 in simian immunodeficiency virus encephalitis leads to repression of sirtuin1. FASEB J 27:3720–3729CrossRefPubMedPubMedCentral
26.
go back to reference Xu R, Bi C, Song J, Wang L, Ge C, Liu X, Zhang M (2015) Upregulation of miR-142-5p in atherosclerotic plaques and regulation of oxidized low-density lipoprotein-induced apoptosis in macrophages. Mol Med Rep 11:3229–3234PubMedPubMedCentral Xu R, Bi C, Song J, Wang L, Ge C, Liu X, Zhang M (2015) Upregulation of miR-142-5p in atherosclerotic plaques and regulation of oxidized low-density lipoprotein-induced apoptosis in macrophages. Mol Med Rep 11:3229–3234PubMedPubMedCentral
27.
go back to reference Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, Lovat F, LeBlanc K, Palatini J, Randall RL et al (2012) miRNA signatures associate with pathogenesis and progression of osteosarcoma. Cancer Res 72:1865–1877CrossRefPubMedPubMedCentral Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, Lovat F, LeBlanc K, Palatini J, Randall RL et al (2012) miRNA signatures associate with pathogenesis and progression of osteosarcoma. Cancer Res 72:1865–1877CrossRefPubMedPubMedCentral
28.
go back to reference Zhao R, Zhu Y, Sun B (2015) Exploration of the effect of mmu-miR-142-5p on osteoblast and the mechanism. Cell Biochem Biophys 71:255–260CrossRefPubMed Zhao R, Zhu Y, Sun B (2015) Exploration of the effect of mmu-miR-142-5p on osteoblast and the mechanism. Cell Biochem Biophys 71:255–260CrossRefPubMed
29.
go back to reference Manigrasso MB, O’Connor JP (2004) Characterization of a closed femur fracture model in mice. J Orthop Trauma 18:687–695CrossRefPubMed Manigrasso MB, O’Connor JP (2004) Characterization of a closed femur fracture model in mice. J Orthop Trauma 18:687–695CrossRefPubMed
30.
go back to reference Cho TJ, Gerstenfeld LC, Einhorn TA (2002) Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 17:513–520CrossRefPubMed Cho TJ, Gerstenfeld LC, Einhorn TA (2002) Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 17:513–520CrossRefPubMed
31.
go back to reference Garcia DM, Baek D, Shin C, Bell GW, Grimson A, Bartel DP (2011) Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nat Struct Mol Biol 18:1139–1146CrossRefPubMedPubMedCentral Garcia DM, Baek D, Shin C, Bell GW, Grimson A, Bartel DP (2011) Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nat Struct Mol Biol 18:1139–1146CrossRefPubMedPubMedCentral
32.
go back to reference Shu L, Zhang H, Boyce BF, Xing L (2013) Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration. J Bone Miner Res 28:1925–1935CrossRefPubMedPubMedCentral Shu L, Zhang H, Boyce BF, Xing L (2013) Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration. J Bone Miner Res 28:1925–1935CrossRefPubMedPubMedCentral
34.
go back to reference Ferguson CM, Miclau T, Hu D, Alpern E, Helms JA (1998) Common molecular pathways in skeletal morphogenesis and repair. Ann N Y Acad Sci 857:33–42CrossRefPubMed Ferguson CM, Miclau T, Hu D, Alpern E, Helms JA (1998) Common molecular pathways in skeletal morphogenesis and repair. Ann N Y Acad Sci 857:33–42CrossRefPubMed
35.
go back to reference Einhorn TA (1998) The cell and molecular biology of fracture healing. Clin Orthop Relat Res (355 Suppl):S7–S21 Einhorn TA (1998) The cell and molecular biology of fracture healing. Clin Orthop Relat Res (355 Suppl):S7–S21
36.
go back to reference Hassan MQ, Gordon JA, Beloti MM, Croce CM, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2010) A network connecting Runx2, SATB2, and the miR-23a–27a–24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci U S A 107:19879–19884CrossRefPubMedPubMedCentral Hassan MQ, Gordon JA, Beloti MM, Croce CM, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2010) A network connecting Runx2, SATB2, and the miR-23a–27a–24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci U S A 107:19879–19884CrossRefPubMedPubMedCentral
37.
go back to reference Li Z, Hassan MQ, Jafferji M, Aqeilan RI, Garzon R, Croce CM, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2009) Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J Biol Chem 284:15676–15684CrossRefPubMedPubMedCentral Li Z, Hassan MQ, Jafferji M, Aqeilan RI, Garzon R, Croce CM, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2009) Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation. J Biol Chem 284:15676–15684CrossRefPubMedPubMedCentral
38.
go back to reference Zhang Y, Xie RL, Croce CM, Stein JL, Lian JB, van Wijnen AJ, Stein GS (2011) A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc Natl Acad Sci U S A 108:9863–9868CrossRefPubMedPubMedCentral Zhang Y, Xie RL, Croce CM, Stein JL, Lian JB, van Wijnen AJ, Stein GS (2011) A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc Natl Acad Sci U S A 108:9863–9868CrossRefPubMedPubMedCentral
39.
go back to reference Yang L, Cheng P, Chen C, He HB, Xie GQ, Zhou HD, Xie H, Wu XP, Luo XH (2012) miR-93/Sp7 function loop mediates osteoblast mineralization. J Bone Miner Res 27:1598–1606CrossRefPubMed Yang L, Cheng P, Chen C, He HB, Xie GQ, Zhou HD, Xie H, Wu XP, Luo XH (2012) miR-93/Sp7 function loop mediates osteoblast mineralization. J Bone Miner Res 27:1598–1606CrossRefPubMed
40.
go back to reference Vimalraj S, Selvamurugan N (2013) MicroRNAs: synthesis, gene regulation and osteoblast differentiation. Curr Issues Mol Biol 15:7–18PubMed Vimalraj S, Selvamurugan N (2013) MicroRNAs: synthesis, gene regulation and osteoblast differentiation. Curr Issues Mol Biol 15:7–18PubMed
41.
go back to reference Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113:25–36CrossRefPubMed Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113:25–36CrossRefPubMed
42.
go back to reference Chen X (2004) A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development. Science 303:2022–2025CrossRefPubMed Chen X (2004) A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development. Science 303:2022–2025CrossRefPubMed
43.
go back to reference Olsen PH, Ambros V (1999) The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev Biol 216:671–680CrossRefPubMed Olsen PH, Ambros V (1999) The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev Biol 216:671–680CrossRefPubMed
44.
go back to reference Zhao L, Huang J, Zhang H, Wang Y, Matesic LE, Takahata M, Awad H, Chen D, Xing L (2011) Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells 29:1601–1610CrossRefPubMedPubMedCentral Zhao L, Huang J, Zhang H, Wang Y, Matesic LE, Takahata M, Awad H, Chen D, Xing L (2011) Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells 29:1601–1610CrossRefPubMedPubMedCentral
Metadata
Title
MiR-142-5p promotes bone repair by maintaining osteoblast activity
Authors
Manli Tu
Juanjuan Tang
Hongbo He
Peng Cheng
Chao Chen
Publication date
01-05-2017
Publisher
Springer Japan
Published in
Journal of Bone and Mineral Metabolism / Issue 3/2017
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-016-0757-8

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