MicroRNA-140 provides robustness to the regulation of hypertrophic chondrocyte differentiation by the PTHrP-HDAC4 pathway

Garyfallia Papaioannou, Fatemeh Mirzamohammadi, Thomas S. Lisse, Shigeki Nishimori, Marc N. Wein, Tatsuya Kobayashi

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Growth plate chondrocytes go through multiple differentiation steps and eventually become hypertrophic chondrocytes. The parathyroid hormone (PTH)-related peptide (PTHrP) signaling pathway plays a central role in regulation of hypertrophic differentiation, at least in part, through enhancing activity of histone deacetylase 4 (HDAC4), a negative regulator of MEF2 transcription factors that drive hypertrophy. We have previously shown that loss of the chondrocyte-specific microRNA (miRNA), miR-140, alters chondrocyte differentiation including mild acceleration of hypertrophic differentiation. Here, we provide evidence that miR-140 interacts with the PTHrP-HDAC4 pathway to control chondrocyte differentiation. Heterozygosity of PTHrP or HDAC4 substantially impaired animal growth in miR-140 deficiency, whereas these mutations had no effect in the presence of miR-140. miR-140-deficient chondrocytes showed increased MEF2C expression with normal levels of total and phosphorylated HDAC4, indicating that the miR-140 pathway merges with the PTHrP-HDAC4 pathway at the level of MEF2C. miR-140 negatively regulated p38 mitogen-activated protein kinase (MAPK) signaling, and inhibition of p38 MAPK signaling reduced MEF2C expression. These results demonstrate that miR-140 ensures the robustness of the PTHrP/HDAC4 regulatory system by suppressing MEF2C-inducing stimuli.

Original languageEnglish (US)
Pages (from-to)1044-1052
Number of pages9
JournalJournal of Bone and Mineral Research
Volume30
Issue number6
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

Keywords

  • BONE MODELING AND REMODELING
  • CELL/TISSUE SIGNALING
  • DEVELOPMENT
  • EPIGENETICS
  • GENETIC ANIMAL MODELS
  • GROWTH PLATE
  • MOLECULAR PATHWAYS
  • PARACRINE PATHWAYS
  • PTHRP

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Fingerprint

Dive into the research topics of 'MicroRNA-140 provides robustness to the regulation of hypertrophic chondrocyte differentiation by the PTHrP-HDAC4 pathway'. Together they form a unique fingerprint.

Cite this