A network connecting Runx2, SATB2, and the miR-23a∼27a∼24-2 cluster regulates the osteoblast differentiation program

Mohammad Q. Hassan, Jonathan A.R. Gordon, Marcio M. Beloti, Carlo M. Croce, Andre J. Van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian

Research output: Contribution to journalArticle

247 Scopus citations

Abstract

Induced osteogenesis includes a program of microRNAs (miRs) to repress the translation of genes that act as inhibitors of bone formation. How expression of bone-related miRs is regulated remains a compelling question. Here we report that Runx2, a transcription factor essential for osteoblastogenesis, negatively regulates expression of the miR cluster 23a∼27a∼24-2. Overexpression, reporter, and chromatin immunoprecipitation assays established the presence of a functional Runx binding element that represses expression of these miRs. Consistent with this finding, exogenous expression of each of the miRs suppressed osteoblast differentiation, whereas antagomirs increased bone marker expression. The biological significance of Runx2 repression of this miR cluster is that each miR directly targets the 3' UTR of SATB2, which is known to synergize with Runx2 to facilitate bone formation. The findings suggest Runx2-negative regulation of multiple miRs by a feedforward mechanism to cause derepression of SATB2 to promote differentiation. We find also that miR-23a represses Runx2 in the terminally differentiated osteocyte, representing a feedback mechanism to attenuate osteoblast maturation. We provide direct evidence for an interdependent relationship among transcriptional inhibition of the miR cluster by Runx2, translational repression of Runx2 and of SATB2 by the cluster miRs during progression of osteoblast differentiation. Furthermore, miR cluster gain of function (i.e., inhibition of osteogenesis) is rescued by the exogenous expression of SATB2. Taken together, we have established a regulatory network with a central role for the miR cluster 23a∼27a∼24-2 in both progression and maintenance of the osteocyte phenotype.

Original languageEnglish (US)
Pages (from-to)19879-19884
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number46
DOIs
StatePublished - Nov 16 2010

Keywords

  • Bone formation by miRs
  • Feed forward-feedback miR control SATB2 targeted by cluster miRs
  • Runx2-regulation of microRNA cluster phenotype attenuation by miRs

ASJC Scopus subject areas

  • General

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