MicroRNA‐140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP‐HDAC4 Pathway

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. © 2014 American Society for Bone and Mineral Research © 2015 American Society for Bone and Mineral Research