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  • Review Article
  • Published:

MicroRNA control of bone formation and homeostasis

Abstract

MicroRNAs (miRNAs) repress cellular protein levels to provide a sophisticated parameter of gene regulation that coordinates a broad spectrum of biological processes. Bone organogenesis is a complex process involving the differentiation and crosstalk of multiple cell types for formation and remodeling of the skeleton. Inhibition of mRNA translation by miRNAs has emerged as an important regulator of developmental osteogenic signaling pathways, osteoblast growth and differentiation, osteoclast-mediated bone resorption activity and bone homeostasis in the adult skeleton. miRNAs control multiple layers of gene regulation for bone development and postnatal functions, from the initial response of stem/progenitor cells to the structural and metabolic activity of the mature tissue. This Review brings into focus an emerging concept of bone-regulating miRNAs, the evidence for which has been gathered largely from in vivo mouse models and in vitro studies in human and mouse skeletal cell populations. Characterization of miRNAs that operate through tissue-specific transcription factors in osteoblast and osteoclast lineage cells, as well as intricate feedforward and reverse loops, has provided novel insights into the supervision of signaling pathways and regulatory networks controlling normal bone formation and turnover. The current knowledge of miRNAs characteristic of human pathologic disorders of the skeleton is presented with a future goal towards translational studies.

Key Points

  • Depletion of microRNAs (miRNAs) in osteoblast lineage cells by conditional deletion of the miRNA-processing endoribonuclease Dicer enzyme reveals a requirement for miRNAs in embryonic bone development and bone homeostasis in the adult skeleton

  • miRNAs highly expressed in mesenchymal progenitor cells are downregulated by osteogenic signals to derepress the regulatory components of pathways essential for osteoblast differentiation

  • Different subsets of bone-regulating miRNAs (designated 'osteomiRs'), are expressed during stages of osteoblast maturation and osteoclastogenesis to regulate the timing and progression of differentiation programs

  • Signaling and transcriptional pathways required for the normal pace of bone formation are simultaneously regulated by a multiplicity of miRNAs that target different components of the same and/or different pathways

  • The Runx2 bone essential transcription factor (also known as AML3 or Cbfa1) is regulated by numerous miRNAs that are selectively expressed in pluripotent mesenchymal and nonosseous cells to suppress the bone phenotype, which simultaneously supports maintenance of alternate cell fates

  • A large cohort of miRNAs is upregulated in mature osteoblasts and osteocytes during the mineralization stage of bone formation to dampen expression of extracellular matrix components and osteogenic factors for limiting bone mass

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Figure 1: The bone remodeling cycle and regulation of bone tissue homeostasis.
Figure 2: The osteoblast differentiation program.
Figure 3: Osteoclast differentiation sequence and effect of microRNAs.
Figure 4: Effect of microRNAs (miRNAs) on osteoblast differentiation.
Figure 5: Regulatory circuits operating in osteoblast lineage cells.
Figure 6: Allocation of mesenchymal stem cells (MSCs) to lineage-specific phenotypes by transcription factors and microRNAs.
Figure 7: MicroRNAs (miRNAs) regulating Runx2.

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Acknowledgements

The authors' work was supported by NIH grants DE012528, AR039588, AR049069 and AR048818. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

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All authors researched the data for the article and provided a substantial contribution to discussions of the content. J. B. Lian, G. S. Stein, A. J. van Wijnen and J. L. Stein wrote the article and reviewed/edited the manuscript before submission.

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Correspondence to Jane B. Lian.

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Supplementary Table 1

Functional microRNAs in the Skeleton (DOC 59 kb)

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Lian, J., Stein, G., van Wijnen, A. et al. MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol 8, 212–227 (2012). https://doi.org/10.1038/nrendo.2011.234

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