MicroRNA-433 Dampens Glucocorticoid Receptor Signaling, Impacting Circadian Rhythm and Osteoblastic Gene Expression

Spenser S Smith, Neha S Dole, Tiziana Franceschetti, Henry C Hrdlicka, Anne M Delany

Research output: Contribution to journalArticle

13 Citations (Scopus)
3 Downloads (Pure)

Abstract

Serum glucocorticoids play a critical role in synchronizing circadian rhythm in peripheral tissues, and multiple mechanisms regulate tissue sensitivity to glucocorticoids. In the skeleton, circadian rhythm helps coordinate bone formation and resorption. Circadian rhythm is regulated through transcriptional and post-transcriptional feedback loops that include microRNAs. How microRNAs regulate circadian rhythm in bone is unexplored. We show that in mouse calvaria, miR-433 displays robust circadian rhythm, peaking just after dark. In C3H/10T1/2 cells synchronized with a pulse of dexamethasone, inhibition of miR-433 using a tough decoy altered the period and amplitude of Per2 gene expression, suggesting that miR-433 regulates rhythm. Although miR-433 does not directly target the Per2 3 'UTR, it does target 2 rhythmically expressed genes in calvaria, Igf1 and Hif1α;. miR-433 can target the glucocorticoid receptor; however glucocorticoid receptor protein abundance was unaffected in miR-433 decoy cells. Rather, miR-433 inhibition dramatically enhanced glucocorticoid signaling due to increased nuclear receptor translocation, activating glucocorticoid receptor transcriptional targets. Lastly, in calvaria of transgenic mice expressing a miR-433 decoy in osteoblastic cells (Col3.6 promoter), the amplitude of Per2 and Bmal1 mRNA rhythm was increased, confirming that miR-433 regulates circadian rhythm. miR-433 was previously shown to target Runx2, and mRNA for Runx2 and its downstream target, osteocalcin were also increased in miR-433 decoy mouse calvaria. We hypothesize that miR-433 helps maintain circadian rhythm in osteoblasts by regulating sensitivity to glucocorticoid receptor signaling.

Original languageEnglish
Pages (from-to)21717-21728
Number of pages12
JournalThe Journal of Biological Chemistry
Volume291
Issue number41
Early online date22 Aug 2016
DOIs
Publication statusPublished - 7 Oct 2016

Fingerprint

Glucocorticoid Receptors
Circadian Rhythm
MicroRNAs
Gene expression
Glucocorticoids
Gene Expression
Skull
Bone
Tissue
Messenger RNA
Osteocalcin
Osteoblasts
3' Untranslated Regions
Cytoplasmic and Nuclear Receptors
Dexamethasone
Genes
Display devices
Feedback
Bone Resorption
Osteogenesis

Keywords

  • bone
  • circadian
  • circadian rhythm
  • glucocorticoid receptor
  • microRNA (miRNA)
  • microRNA mechanism
  • osteoblast
  • post-transcriptional regulation

Cite this

MicroRNA-433 Dampens Glucocorticoid Receptor Signaling, Impacting Circadian Rhythm and Osteoblastic Gene Expression. / Smith, Spenser S; Dole, Neha S; Franceschetti, Tiziana; Hrdlicka, Henry C; Delany, Anne M.

In: The Journal of Biological Chemistry, Vol. 291, No. 41, 07.10.2016, p. 21717-21728.

Research output: Contribution to journalArticle

Smith, Spenser S ; Dole, Neha S ; Franceschetti, Tiziana ; Hrdlicka, Henry C ; Delany, Anne M. / MicroRNA-433 Dampens Glucocorticoid Receptor Signaling, Impacting Circadian Rhythm and Osteoblastic Gene Expression. In: The Journal of Biological Chemistry. 2016 ; Vol. 291, No. 41. pp. 21717-21728.
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abstract = "Serum glucocorticoids play a critical role in synchronizing circadian rhythm in peripheral tissues, and multiple mechanisms regulate tissue sensitivity to glucocorticoids. In the skeleton, circadian rhythm helps coordinate bone formation and resorption. Circadian rhythm is regulated through transcriptional and post-transcriptional feedback loops that include microRNAs. How microRNAs regulate circadian rhythm in bone is unexplored. We show that in mouse calvaria, miR-433 displays robust circadian rhythm, peaking just after dark. In C3H/10T1/2 cells synchronized with a pulse of dexamethasone, inhibition of miR-433 using a tough decoy altered the period and amplitude of Per2 gene expression, suggesting that miR-433 regulates rhythm. Although miR-433 does not directly target the Per2 3 'UTR, it does target 2 rhythmically expressed genes in calvaria, Igf1 and Hif1α;. miR-433 can target the glucocorticoid receptor; however glucocorticoid receptor protein abundance was unaffected in miR-433 decoy cells. Rather, miR-433 inhibition dramatically enhanced glucocorticoid signaling due to increased nuclear receptor translocation, activating glucocorticoid receptor transcriptional targets. Lastly, in calvaria of transgenic mice expressing a miR-433 decoy in osteoblastic cells (Col3.6 promoter), the amplitude of Per2 and Bmal1 mRNA rhythm was increased, confirming that miR-433 regulates circadian rhythm. miR-433 was previously shown to target Runx2, and mRNA for Runx2 and its downstream target, osteocalcin were also increased in miR-433 decoy mouse calvaria. We hypothesize that miR-433 helps maintain circadian rhythm in osteoblasts by regulating sensitivity to glucocorticoid receptor signaling.",
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N1 - FUNDING This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [AR44877]; the National Institutes for Dental and Craniofacial Research [5T90DE21989]; a Grant-in-Aid award from the American Society for Bone and Mineral Research; the UConn Health Center Research Advisory council; and the Center for Molecular Medicine at UConn Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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