The Expression and Function of Metastases Associated Lung Adenocarcinoma Transcript-1 Long Non-Coding RNA in Subchondral Bone and Osteoblasts from Patients with Osteoarthritis.

Fawzeyah A Alnajjar,Hussein Farah,Archana Sharma-Oates,Tom Nicholson,Dominika E Nanus,Simon W Jones,Edward T Davis,Susanne N Wijesinghe

doi:10.3390/cells10040786

Abstract

Metastasis Associated Lung Adenocarcinoma Transcript-1 (MALAT1) is implicated in regulating the inflammatory response and in the pathology of several chronic inflammatory diseases, including osteoarthritis (OA). The purpose of this study was to examine the relationship between OA subchondral bone expression of MALAT1 with parameters of joint health and biomarkers of joint inflammation, and to determine its functional role in human OA osteoblasts. Subchondral bone and blood were collected from hip and knee OA patients (n = 17) and bone only from neck of femur fracture patients (n = 6) undergoing joint replacement surgery. Cytokines were determined by multiplex assays and ELISA, and gene expression by qPCR. MALAT1 loss of function was performed in OA patient osteoblasts using locked nucleic acids. The osteoblast transcriptome was analysed by RNASeq and pathway analysis. Bone expression of MALAT1 positively correlated to serum DKK1 and galectin-1 concentrations, and in OA patient osteoblasts was induced in response to IL-1β stimulation. Osteoblasts depleted of MALAT1 exhibited differential expression (>1.5 fold change) of 155 genes, including PTGS2. Both basal and IL-1β-mediated PGE2 secretion was greater in MALAT1 depleted osteoblasts. The induction of MALAT1 in human OA osteoblasts upon inflammatory challenge and its modulation of PGE2 production suggests that MALAT1 may play a role in regulating inflammation in OA subchondral bone.

Highlights

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of pain and disability for which there are currently no approved pharmacological disease modifying therapeutics [1]
Metastasis Associated Lung Adenocarcinoma Transcript-1 (MALAT1) was highly expressed in OA subchondral bone tissue, with on average greater expression in hip OA compared to non-OA hip (NOF#)
We examined whether the subchondral bone expression of MALAT1 was related to biomarkers of inflammation by measuring the concentration of a panel of 22 cytokines in OA patient serum by Luminex

Summary

Introduction

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of pain and disability for which there are currently no approved pharmacological disease modifying therapeutics [1]. Non-pharmacological therapeutic strategies such as platelet rich plasma and mesenchymal stem cells, aimed at promoting cartilage repair, hold promise but require further clinical studies to confirm efficacy and safety [4]. Despite initially considered to be a disease solely of the articular cartilage, it is widely accepted that OA is a disease that encompasses the whole joint, including underlying subchondral bone tissue [2]. Pathological changes to OA subchondral bone tissue, characterised by trabecular thickening [6], abnormal type I Collagen production [7,8]

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