LncRNA HOXA-AS2 positively regulates osteogenesis of mesenchymal stem cells through inactivating NF-κB signalling.

Xinxing Zhu,Jinjin Yu,Genshen Zhong,Jiang Du,Juntang Lin,Liang Qiao

doi:10.1111/jcmm.14034

Abstract

As is previously reported, mesenchymal stem cells have potential ability to differentiate into osteocytes. However, the underlying mechanism during this biological process is poorly understood. In the present study, we identify a novel long non‐coding RNA named HOXA‐AS2 as a critical regulator during the formation of osteogenesis. Attenuation of HOXA‐AS2 can reduce the calcium deposition and repress the alkaline phosphatase activity. Moreover, the expressions of osteogenic marker genes are markedly downregulated after HOXA‐AS2 depletion. Mechanistically, we found HOXA‐AS2 can regulate the transcriptional activity of NF‐κB, a critical inhibitor of osteogenesis. More importantly, HOXA‐AS2 knockdown could result in the transcriptional repression of the osteogenic master transcription factor SP7 by a NF‐κB/HDAC2‐coordinated H3K27 deacetylation mechanism. Based on these studies, we conclude that HOXA‐AS2 may serve as a promising therapeutic target for bone tissue repair and regeneration in the near future.

Highlights

Mesenchymal stem cells (MSCs), a group of cells with excellent proliferation and multiple differentiation capacities, can be isolated from adipose tissue, bone marrow and many other tissues
We determined the underlying mechanism by which HOXA‐AS2 regulates osteogenic differentiation of MSCs and discovered HOXA‐AS2 can epigenetically mediate the expression of the osteogenic master transcription factor SP7 in a NF‐κB and HDAC2‐coordinated manner
We found the expression of HOXA‐AS2 is dramatically reduced in both mesenchymal stem cells (MenSCs) and umbilical cord mesenchymal stem cells (UCMSCs) upon osteogenic media induction (Figure 1A,B), indicating HOXA‐AS2 may act as a crucial regulator participating in the osteogenic regulation

Summary

| INTRODUCTION

Mesenchymal stem cells (MSCs), a group of cells with excellent proliferation and multiple differentiation capacities, can be isolated from adipose tissue, bone marrow and many other tissues. A variety of lncRNAs were well investigated and found to play critical regulatory roles during MSC differentiation, such as a recently identified lncRNA named PU.1‐as, a antisense transcript of the PU.[1] gene, can prevent PU.[1] mRNA translation by forming a mRNA/AS lncRNA duplex, promotes adipogenesis of MSCs.[26]. Another well studied lncRNA is ANCR, which could negatively regulate the osteogenic differentiation, enforced overexpression of ANCR can inhibit osteogenesis through EZH2‐ mediated transcriptional repression of RUNX2.27. We determined the underlying mechanism by which HOXA‐AS2 regulates osteogenic differentiation of MSCs and discovered HOXA‐AS2 can epigenetically mediate the expression of the osteogenic master transcription factor SP7 in a NF‐κB and HDAC2‐coordinated manner

| MATERIAL AND METHODS

| RESULTS

Findings

| DISCUSSION