Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a novReportar como inadecuado




Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: a nov - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Arthritis Research and Therapy

, 16:491

First Online: 26 November 2014Received: 11 March 2014Accepted: 12 November 2014

Abstract

IntroductionTo investigate if decreased histone deacetylase 4 HDAC4 is associated with human osteoarthritis OA cartilage degeneration by releasing HDAC4 inhibition of runt-related transcription factor-2 Runx2 resulting in increase of OA cartilage degeneration-related genes.

MethodsThe mRNA and protein levels of HDAC4, Runx2, matrix metalloproteinase MMP-13, Indian hedgehog Ihh and type X collagen were detected by performing real-time PCR RT-PCR, western blotting and immunohistochemistry on specimens from human OA and normal cartilage. To further explore the mechanism of regulation of Runx2 and OA-related genes by HDAC4, changes in these OA-related genes were further quantified by RT-PCR after overexpression of HDAC4 and knockdown of HDAC4 by siRNA. Runx2 and MMP-13 promoter activities were measured by dual luciferase assays.

ResultsThe levels of HDAC4 in the cartilage from OA patients and healthy 40- to 60-year-old donors were decreased to 31% and 65% compared with specimens from 20- to 40-year-old healthy donors, respectively P <0.05. Decreased HDAC4 was associated with increased Runx2 and other OA-related genes in human OA cartilage, specifically: MMP-13, Ihh and type X collagen. Exogenous HDAC4 decreased the mRNA levels of Runx2, MMP1, MMP3, MMP-13, type X collagen, Ihh, ADAMTS-4 and -5, and increased the mRNA of type II collagen. In addition, the data also shows that overexpression of HDAC4 not only decreased the expression of interleukin IL-1β, Cox2 and iNos and increased the expression of aggrecan, but also partially blocked the effect of IL-1β on expression of catabolic events in human OA chondrocytes. HDAC4 also inhibited Runx2 promoter activity and MMP13 promotor activity in a dose-dependent manner. In contrast, inhibition of HDAC4 by TSA drug had an opposite effect.

ConclusionsOur study is the first to demonstrate that decreased HDAC4 contributes, at least in part, to the pathogenesis of OA cartilage degeneration. Thus, HDAC4 may have chondroprotective properties by inhibiting Runx2 and OA-related genes.

AbbreviationsANOVAanalysis of variance

DMEMDulbecco’s modified Eagle’s medium

FBSfetal bovine serum

GEPgreen fluorescent protein

HDAC4histone deacetylase 4

IgGimmunoglobulin G

ILinterleukin

MMPsmatrix metalloproteases

OAosteoarthritis

PBSphosphate-buffered saline

Runx2runt-related transcription factor-2

SDstandard deviation

siRNAsmall interfering RNA

TBSTris-buffered saline

TSAtrichostatin A

Electronic supplementary materialThe online version of this article doi:10.1186-s13075-014-0491-3 contains supplementary material, which is available to authorized users.

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Autor: Kun Cao - Lei Wei - Zhiqiang Zhang - Li Guo - Congming Zhang - Yongping Li - Changqi Sun - Xiaojuan Sun - Shaowei Wang -

Fuente: https://link.springer.com/







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