title: MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway.
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. © 2014 American Society for Bone and Mineral Research © 2015 American Society for Bone and Mineral Research.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Garyfallia
authors.initials: G
authors.lastname: Papaioannou
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Mirzamohammadi
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lisse
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nishimori
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Marc N
authors.initials: MN
authors.lastname: Wein
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064326:MEF2 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D064326:MEF2 Transcription Factors; C547828:MIRN140 microRNA, mouse; C578041:Mef2c protein, mouse; D035683:MicroRNAs; D044162:Parathyroid Hormone-Related Protein; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: BONE MODELING AND REMODELING; CELL/TISSUE SIGNALING; DEVELOPMENT; EPIGENETICS; GENETIC ANIMAL MODELS; GROWTH PLATE; MOLECULAR PATHWAYS; PARACRINE PATHWAYS; PTHRP