MicroRNAs Are Critical Regulators of Osteoclast Differentiation
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Purpose of Review
Our goal is to comprehensively review the most recent reports of microRNA (miRNA) regulation of osteoclastogenesis. We highlight validated miRNA-target interactions and their place in the signaling networks controlling osteoclast differentiation and function.
Using unbiased approaches to identify miRNAs of interest and reporter-3′UTR assays to validate interactions, recent studies have elucidated the impact of specific miRNA-mRNA interactions during in vitro osteoclastogenesis. There has been a focus on signaling mediators downstream of the RANK and CSF1R signaling, and genes essential for differentiation and function. For example, several miRNAs directly and indirectly target the master osteoclast transcription factor, Nfatc1 (e.g., miR-124 and miR-214) and Rho-GTPases, Cdc42, and Rac1 (e.g., miR-29 family).
Validating miRNA expression patterns, targets, and impact in osteoclasts and other skeletal cells is critical for understanding basic bone biology and for fulfilling the therapeutic potential of miRNA-based strategies in the treatment bone diseases.
KeywordsOsteoclast Differentiation Fusion miRNA Non-coding RNA Microarray
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Dr. Julia Charles (Brigham and Women’s Hospital, Boston, MA) for her careful review of the manuscript.
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [AR064867, AMD/SKL]; the National Institutes for Dental and Craniofacial Research [T90DE21989]; and the Center for Molecular Oncology at UConn Health.
Compliance with Ethical Standards
Conflict of Interest
Henry C. Hrdlicka, Sun-Kyeong Lee, and Anne M. Delany each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Long CL, Humphrey MB. Osteoimmunology: the expanding role of immunoreceptors in osteoclasts and bone remodeling. Bonekey Rep. 2012;1:59.Google Scholar
- 3.Schett G. Effects of inflammatory and anti-inflammatory cytokines on the bone. Eur J Clin Investig. 2011;41(12):1361–6.Google Scholar
- 16.•• de la Rica L, Garcia-Gomez A, Comet NR, Rodriguez-Ubreva J, Ciudad L, Vento-Tormo R, et al. NF-kappaB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation. Genome Biol. 2015;16:2 This study extensively characterizes miRNA expression profiles during osteoclastogenesis and demonstrates the necessity of NFκB transcription factor activity for the upregulation of various pro-osteoclast miRNAs. PubMedPubMedCentralGoogle Scholar
- 19.• Guo LJ, Liao L, Yang L, Li Y, Jiang TJ. MiR-125a TNF receptor-associated factor 6 to inhibit osteoclastogenesis. Exp Cell Res. 2014;321(2):142–52 This report provides a thorough schematic for investigating the general role of a miRNA during osteoclastogenesis, its targets, and its broader mechanism of action. PubMedGoogle Scholar
- 20.Lee Y, Kim HJ, Park CK, Kim YG, Lee HJ, Kim JY, et al. MicroRNA-124 regulates osteoclast differentiation. Bone. 2013;56(2):383–9.Google Scholar
- 23.Zhao, H, Zhang, J, Shao, H, Liu, J, Jin, M, Chen, J, and Huang, Y. miRNA-340 inhibits osteoclast differentiation via repression of MITF. Biosci Rep, 2017;37(4). https://doi.org/10.1042/BSR20170302
- 34.Lutter AH, Hempel U, Anderer U, Dieter P. Biphasic influence of PGE2 on the resorption activity of osteoclast-like cells derived from human peripheral blood monocytes and mouse RAW264.7 cells. Prostaglandins Leukot Essent Fat Acids. 2016;111:1–7.Google Scholar
- 36.Kaneko H, Mehrotra M, Alander C, Lerner U, Pilbeam C, Raisz L. Effects of prostaglandin E2 and lipopolysaccharide on osteoclastogenesis in RAW 264.7 cells. Prostaglandins Leukot Essent Fat Acids. 2007;77(3–4):181–6.Google Scholar
- 42.• Cheng P, Chen C, He HB, Hu R, Zhou HD, Xie H, et al. miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B. J Bone Miner Res. 2013;28(5):1180–90 This work illustrates an excellent experimental approach for first identifiying a miRNA of interest and subsequently studying its role in vitro and in vivo.PubMedGoogle Scholar
- 67.•• Dou C, Cao Z, Yang B, Ding N, Hou T, Luo F, et al. Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis. Sci Rep. 2016;6:21499 This study lays important ground work for studying more expansive non-coding RNA networks, including miRNAs that may be regulating osteoclast differentiation. PubMedPubMedCentralGoogle Scholar
- 78.• Dang L, Liu J, Li F, Wang L, Li D, Guo B, et al. Targeted delivery systems for molecular therapy in skeletal disorders. Int J Mol Sci. 2016;17(3):428 This paper concisely reviews the currently known and utilized methods for targeting small molecules to the bone surface. PubMedPubMedCentralGoogle Scholar
- 79.•• Liu J, Dang L, Li D, Liang C, He X, Wu H, et al. A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts. Biomaterials. 2015;52:148–60 This study provides a thorough outline for future work in miRNA delivery to the bone surface. PubMedGoogle Scholar