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Published in: Current Osteoporosis Reports 1/2018

01-02-2018 | Genetics (M Johnson and S Ralston, Section Editors)

Regulation of Bone Metabolism by microRNAs

Author: Hanna Taipaleenmäki

Published in: Current Osteoporosis Reports | Issue 1/2018

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Abstract

Purpose of Review

The small non-coding microRNAs (miRNAs) have emerged as important post-transcriptional regulators of various physiological and pathological processes. The purpose of this article is to review the important recent advances on the role of miRNAs in bone remodeling and metabolic bone disorders.

Recent Findings

In a physiological context, miRNAs regulate bone formation and bone resorption, thereby contributing to the maintenance of bone homeostasis. Under pathological conditions, an aberrant miRNA signaling contributes to the onset and progression of skeletal disorders, such as osteoporosis. Furthermore, miRNAs can be secreted to circulation and have clinical potential as non-invasive biomarkers. In a therapeutic setting, miRNA delivery or antagonism has been reported to affect several diseases under pre-clinical conditions thereby emerging as novel pharmacological tools.

Summary

miRNAs are key regulators of bone remodeling in health and disease. The future perspectives in the field include the role of secreted miRNAs in cell-cell communication in the bone environment. Furthermore, the clinical potential of using miRNAs as diagnostic tools and therapeutic targets to treat metabolic bone diseases provides an attractive future direction.
Literature
9.
go back to reference Taipaleenmäki H, Bjerre Hokland L, Chen L, Kauppinen S, Kassem M. Mechanisms in endocrinology: micro-RNAs: targets for enhancing osteoblast differentiation and bone formation. Eur J Endocrinol [Internet]. 2012 Mar [cited 2016 Apr 28];166(3):359–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22084154. Taipaleenmäki H, Bjerre Hokland L, Chen L, Kauppinen S, Kassem M. Mechanisms in endocrinology: micro-RNAs: targets for enhancing osteoblast differentiation and bone formation. Eur J Endocrinol [Internet]. 2012 Mar [cited 2016 Apr 28];166(3):359–71. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22084154.
11.
18.
go back to reference Hassan MQ, Gordon JAR, Beloti MM, Croce CM, Wijnen AJV, Stein JL, et al. A network connecting Runx2, SATB2, and the miR-23a 27a 24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci [Internet]. 2010 Nov 16 [cited 2017 Oct 16];107(46):19879–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20980664. Hassan MQ, Gordon JAR, Beloti MM, Croce CM, Wijnen AJV, Stein JL, et al. A network connecting Runx2, SATB2, and the miR-23a 27a 24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci [Internet]. 2010 Nov 16 [cited 2017 Oct 16];107(46):19879–84. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​20980664.
28.
go back to reference Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol [Internet]. 2007 Jun 7 [cited 2017 Oct 17];9(6):654–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17486113. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol [Internet]. 2007 Jun 7 [cited 2017 Oct 17];9(6):654–9. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​17486113.
29.
33.
go back to reference • Hackl M, Heilmeier U, Weilner S, Grillari J. Circulating microRNAs as novel biomarkers for bone diseases—complex signatures for multifactorial diseases? Mol Cell Endocrinol [Internet]. 2016 Sep 5 [cited 2017 Oct 14];432:83–95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26525415. Review highlighting the role of circulating miRNAs as potential biomarkers in bone disaeses. • Hackl M, Heilmeier U, Weilner S, Grillari J. Circulating microRNAs as novel biomarkers for bone diseases—complex signatures for multifactorial diseases? Mol Cell Endocrinol [Internet]. 2016 Sep 5 [cited 2017 Oct 14];432:83–95. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26525415. Review highlighting the role of circulating miRNAs as potential biomarkers in bone disaeses.
36.
go back to reference Bauer D, Krege J, Lane N, Leary E, Libanati C, Miller P, et al. National Bone Health Alliance Bone Turnover Marker Project: current practices and the need for US harmonization, standardization, and common reference ranges. Osteoporos Int [Internet]. 2012 Oct 14 [cited 2017 Oct 17];23(10):2425–33. Available from: http://link.springer.com/10.1007/s00198-012-2049-z Bauer D, Krege J, Lane N, Leary E, Libanati C, Miller P, et al. National Bone Health Alliance Bone Turnover Marker Project: current practices and the need for US harmonization, standardization, and common reference ranges. Osteoporos Int [Internet]. 2012 Oct 14 [cited 2017 Oct 17];23(10):2425–33. Available from: http://​link.​springer.​com/​10.​1007/​s00198-012-2049-z
40.
go back to reference Ralston SH, Galwey N, MacKay I, Albagha OME, Cardon L, Compston JE, et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet [Internet]. 2005 Apr 1 [cited 2017 Oct 17];14(7):943–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15746152. Ralston SH, Galwey N, MacKay I, Albagha OME, Cardon L, Compston JE, et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet [Internet]. 2005 Apr 1 [cited 2017 Oct 17];14(7):943–51. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​15746152.
41.
go back to reference Hsu Y-H, Zillikens MC, Wilson SG, Farber CR, Demissie S, Soranzo N, et al. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits. Visscher PM, editor. PLoS Genet [Internet]. 2010 Jun 10 [cited 2017 Oct 17];6(6):e1000977. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20548944. Hsu Y-H, Zillikens MC, Wilson SG, Farber CR, Demissie S, Soranzo N, et al. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits. Visscher PM, editor. PLoS Genet [Internet]. 2010 Jun 10 [cited 2017 Oct 17];6(6):e1000977. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​20548944.
42.
go back to reference • Seeliger C, Karpinski K, Haug AT, Vester H, Schmitt A, Bauer JS, et al. Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J Bone Miner Res [Internet]. 2014 Aug [cited 2017 Oct 17];29(8):1718–28. Available from: http://doi.wiley.com/10.1002/jbmr.2175. A study comparing miRNA signatures in serum and bone tissue. • Seeliger C, Karpinski K, Haug AT, Vester H, Schmitt A, Bauer JS, et al. Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J Bone Miner Res [Internet]. 2014 Aug [cited 2017 Oct 17];29(8):1718–28. Available from: http://​doi.​wiley.​com/​10.​1002/​jbmr.​2175. A study comparing miRNA signatures in serum and bone tissue.
44.
go back to reference Kocijan R, Muschitz C, Geiger E, Skalicky S, Baierl A, Dormann R, et al. Circulating microRNA signatures in patients with idiopathic and postmenopausal osteoporosis and fragility fractures. J Clin Endocrinol Metab [Internet]. 2016 Nov [cited 2017 Oct 14];101(11):4125–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27552543. Kocijan R, Muschitz C, Geiger E, Skalicky S, Baierl A, Dormann R, et al. Circulating microRNA signatures in patients with idiopathic and postmenopausal osteoporosis and fragility fractures. J Clin Endocrinol Metab [Internet]. 2016 Nov [cited 2017 Oct 14];101(11):4125–34. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27552543.
45.
go back to reference • Heilmeier U, Hackl M, Skalicky S, Weilner S, Schroeder F, Vierlinger K, et al. Serum miRNA signatures are indicative of skeletal fractures in postmenopausal women with and without type 2 diabetes and influence osteogenic and adipogenic differentiation of adipose tissue-derived mesenchymal stem cells in vitro. J Bone Miner Res [Internet]. 2016 Dec [cited 2017 Oct 14];31(12):2173–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27345526. A comprehensive study identifying miRNA signatures that are indicative of skeletal fractures in diabetic bone disease and postmenopausal osteoprosis. • Heilmeier U, Hackl M, Skalicky S, Weilner S, Schroeder F, Vierlinger K, et al. Serum miRNA signatures are indicative of skeletal fractures in postmenopausal women with and without type 2 diabetes and influence osteogenic and adipogenic differentiation of adipose tissue-derived mesenchymal stem cells in vitro. J Bone Miner Res [Internet]. 2016 Dec [cited 2017 Oct 14];31(12):2173–92. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27345526. A comprehensive study identifying miRNA signatures that are indicative of skeletal fractures in diabetic bone disease and postmenopausal osteoprosis.
46.
go back to reference Suomi S, Taipaleenmäki H, Seppänen A, Ripatti T, Väänänen K, Hentunen T, et al. MicroRNAs regulate osteogenesis and chondrogenesis of mouse bone marrow stromal cells. Gene Regul Syst Bio [Internet]. 2008 Apr 22 [cited 2017 Oct 17];2:177–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19787082. Suomi S, Taipaleenmäki H, Seppänen A, Ripatti T, Väänänen K, Hentunen T, et al. MicroRNAs regulate osteogenesis and chondrogenesis of mouse bone marrow stromal cells. Gene Regul Syst Bio [Internet]. 2008 Apr 22 [cited 2017 Oct 17];2:177–91. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​19787082.
48.
go back to reference •• Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang T-C, et al. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature [Internet]. 2014 Aug 28 [cited 2017 Oct 17];512(7515):431–5. Available from: http://www.nature.com/doifinder/10.1038/nature13375. By using several genetic and pharmacological approached, this study demonstrates the important role of miR-34a in osteoporosis and bone metastasis. •• Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang T-C, et al. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature [Internet]. 2014 Aug 28 [cited 2017 Oct 17];512(7515):431–5. Available from: http://​www.​nature.​com/​doifinder/​10.​1038/​nature13375. By using several genetic and pharmacological approached, this study demonstrates the important role of miR-34a in osteoporosis and bone metastasis.
50.
go back to reference Shi C, Qi J, Huang P, Jiang M, Zhou Q, Zhou H, et al. MicroRNA-17/20a inhibits glucocorticoid-induced osteoclast differentiation and function through targeting RANKL expression in osteoblast cells. Bone [Internet]. 2014 Nov [cited 2017 Oct 17];68:67–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25138550. Shi C, Qi J, Huang P, Jiang M, Zhou Q, Zhou H, et al. MicroRNA-17/20a inhibits glucocorticoid-induced osteoclast differentiation and function through targeting RANKL expression in osteoblast cells. Bone [Internet]. 2014 Nov [cited 2017 Oct 17];68:67–75. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25138550.
53.
go back to reference Chen L, HolmstrØm K, Qiu W, Ditzel N, Shi K, Hokland L, et al. MicroRNA-34a inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells. Stem Cells [Internet]. 2014 Apr [cited 2017 Oct 17];32(4):902–12. Available from: http://doi.wiley.com/10.1002/stem.1615. Chen L, HolmstrØm K, Qiu W, Ditzel N, Shi K, Hokland L, et al. MicroRNA-34a inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells. Stem Cells [Internet]. 2014 Apr [cited 2017 Oct 17];32(4):902–12. Available from: http://​doi.​wiley.​com/​10.​1002/​stem.​1615.
54.
go back to reference Eskildsen T, Taipaleenmaki H, Stenvang J, Abdallah BM, Ditzel N, Nossent AY, et al. MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci [Internet]. 2011 Apr 12 [cited 2017 Oct 14];108(15):6139–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21444814. Eskildsen T, Taipaleenmaki H, Stenvang J, Abdallah BM, Ditzel N, Nossent AY, et al. MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci [Internet]. 2011 Apr 12 [cited 2017 Oct 14];108(15):6139–44. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​21444814.
55.
go back to reference Li H, Xie H, Liu W, Hu R, Huang B, Tan Y-F, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest [Internet]. 2009 Dec 1 [cited 2017 Oct 17];119(12):3666–77. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19920351. Li H, Xie H, Liu W, Hu R, Huang B, Tan Y-F, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest [Internet]. 2009 Dec 1 [cited 2017 Oct 17];119(12):3666–77. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​19920351.
57.
go back to reference •• Li D, Liu J, Guo B, Liang C, Dang L, Lu C, et al. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat Commun [Internet]. 2016 Mar 7 [cited 2017 Oct 14];7:10872. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26947250. An exiting study demonstrating that secreted miRNAs can regulate cell-cell communication in bone. •• Li D, Liu J, Guo B, Liang C, Dang L, Lu C, et al. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat Commun [Internet]. 2016 Mar 7 [cited 2017 Oct 14];7:10872. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26947250. An exiting study demonstrating that secreted miRNAs can regulate cell-cell communication in bone.
59.
go back to reference Wang F-S, Chuang P-C, Chung P-C, Lin C-L, Chen M-W, Ke H-J, et al. MicroRNA-29a protects against glucocorticoid-induced bone loss and fragility in rats by orchestrating bone acquisition and resorption. Arthritis Rheum [Internet]. 2013 Jun [cited 2017 Oct 17];65(6):1530–40. Available from: http://doi.wiley.com/10.1002/art.37948. Wang F-S, Chuang P-C, Chung P-C, Lin C-L, Chen M-W, Ke H-J, et al. MicroRNA-29a protects against glucocorticoid-induced bone loss and fragility in rats by orchestrating bone acquisition and resorption. Arthritis Rheum [Internet]. 2013 Jun [cited 2017 Oct 17];65(6):1530–40. Available from: http://​doi.​wiley.​com/​10.​1002/​art.​37948.
62.
go back to reference Cheng P, Chen C, He H-B, Hu R, Zhou H-D, Xie H, et al. miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B. J Bone Miner Res [Internet]. 2013 May [cited 2017 Oct 17];28(5):1180–90. Available from: http://doi.wiley.com/10.1002/jbmr.1845 Cheng P, Chen C, He H-B, Hu R, Zhou H-D, Xie H, et al. miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B. J Bone Miner Res [Internet]. 2013 May [cited 2017 Oct 17];28(5):1180–90. Available from: http://​doi.​wiley.​com/​10.​1002/​jbmr.​1845
70.
go back to reference Wang F-S, Chung P-C, Lin C-L, Chen M-W, Ke H-J, Chang Y-H, et al. MicroRNA-29a protects against glucocorticoid-induced bone loss and fragility in rats by orchestrating bone acquisition and resorption. Arthritis Rheum [Internet]. 2013 Jun [cited 2017 Oct 14];65(6):1530–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23529662. Wang F-S, Chung P-C, Lin C-L, Chen M-W, Ke H-J, Chang Y-H, et al. MicroRNA-29a protects against glucocorticoid-induced bone loss and fragility in rats by orchestrating bone acquisition and resorption. Arthritis Rheum [Internet]. 2013 Jun [cited 2017 Oct 14];65(6):1530–40. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23529662.
72.
go back to reference Liu P, Baumgart M, Groth M, Wittmann J, Jäck H-M, Platzer M, et al. Dicer ablation in osteoblasts by Runx2 driven cre-loxP recombination affects bone integrity, but not glucocorticoid-induced suppression of bone formation. Sci Rep [Internet]. 2016 Aug 24 [cited 2017 Oct 17];6(1):32112. Available from: http://www.nature.com/articles/srep32112. Liu P, Baumgart M, Groth M, Wittmann J, Jäck H-M, Platzer M, et al. Dicer ablation in osteoblasts by Runx2 driven cre-loxP recombination affects bone integrity, but not glucocorticoid-induced suppression of bone formation. Sci Rep [Internet]. 2016 Aug 24 [cited 2017 Oct 17];6(1):32112. Available from: http://​www.​nature.​com/​articles/​srep32112.
74.
go back to reference Kong X, Yu J, Bi J, Qi H, Di W, Wu L, et al. Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue. Diabetes [Internet]. 2015 Feb [cited 2017 Oct 17];64(2):393–404. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25187367. Kong X, Yu J, Bi J, Qi H, Di W, Wu L, et al. Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue. Diabetes [Internet]. 2015 Feb [cited 2017 Oct 17];64(2):393–404. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25187367.
75.
78.
go back to reference Dole NS, Kapinas K, Kessler CB, Yee S-P, Adams DJ, Pereira RC, et al. A single nucleotide polymorphism in osteonectin 3′ untranslated region regulates bone volume and is targeted by miR-433. J Bone Miner Res [Internet]. 2015 Apr [cited 2017 Oct 17];30(4):723–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25262637. Dole NS, Kapinas K, Kessler CB, Yee S-P, Adams DJ, Pereira RC, et al. A single nucleotide polymorphism in osteonectin 3′ untranslated region regulates bone volume and is targeted by miR-433. J Bone Miner Res [Internet]. 2015 Apr [cited 2017 Oct 17];30(4):723–32. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25262637.
82.
go back to reference Taipaleenmäki H, Farina NH, van Wijnen AJ, Stein JL, Hesse E, Stein GS, et al. Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget [Internet]. 2016 Oct 12 [cited 2017 Oct 17];7(48):79032–46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27738322. Taipaleenmäki H, Farina NH, van Wijnen AJ, Stein JL, Hesse E, Stein GS, et al. Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget [Internet]. 2016 Oct 12 [cited 2017 Oct 17];7(48):79032–46. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27738322.
Metadata
Title
Regulation of Bone Metabolism by microRNAs
Author
Hanna Taipaleenmäki
Publication date
01-02-2018
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 1/2018
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-018-0417-0

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