The role of the long non-coding RNA MALAT1 in mediating inflammation in the human osteoarthritis joint

Alnajjar, Fawzeyah AQ ORCID: 0000-0003-2472-8971 (2022). The role of the long non-coding RNA MALAT1 in mediating inflammation in the human osteoarthritis joint. University of Birmingham. Ph.D.

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Osteoarthritis (OA) is a common degenerative and painful disorder affecting more than 22% of adults who are older than 40. According to Centre for Disease Control (CDC) 2020, more than 32.5 million US adults have OA. OA is a disease of the whole joint, including the cartilage, subchondral bone, synovium and skeletal muscle, and inflammatory processes contribute to the pathogenesis of the diseased joint tissues. Since lncRNAs have emerged as central regulators of the inflammatory response they may play a key role in mediating OA pathogenesis. For example, the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) lncRNA, has been implicated in contributing to the pathogenesis of many diseases by controlling the epigenetic transcriptional modulation of inflammatory genes in chronic inflammatory diseases. The aim of this thesis was therefore to investigate the role of lncRNAs, and in particular the lncRNA MALAT1, in OA pathogenesis by examining their association with the inflammatory response in OA and their expression in diseased OA joint tissues and OA joint tissue derived cells including synovial fibroblasts, articular chondrocytes and subchondral osteoblasts. In this thesis, I report for the first time the functional role of the lncRNA MALAT1 in OA mature osteoblasts, and the relationship between MALAT1 joint tissue expression and parameters of inflammation. A total of 16 tissues were utilized for the analysis of MALAT1 expression from different BMI cohorts of OA joints including 3 synovial membrane, 8 articular cartilage and 5 subchondral bone and a total of 17 OA patient’s demographic data were used, for articular cartilage and subchondral bone tissues, blood was collected from a total of 17 patients with end-stage OA and 6 non-OA patients from neck of femur fracture (NOF). The results of this thesis project showed that MALAT1 was expressed in all the primary cells obtained from OA joint tissues, and all primary cells induced IL-6 production upon stimulation with human protein recombinant IL-1β (1ng/mL) and TNF-α (10ng/mL). Notably, obese and over-weight OA patient cohorts induced more IL-6, compared to joint cells isolated from normal-weight OA patients. In OA articular cartilage tissues, MALAT1 expression was significantly associated with OA severity parameters in hip and knee joints, and with the levels of circulatory chemokines Dickkopf WNT signaling pathway inhibitor 1 (DKK1), Eotaxin and the levels of MIP3a chemotactic locally. In OA bone tissues MALAT1 expression showed a significant correlation with circulatory DKKI, Galectin1 and TNF-. MALAT1 depletion effects on the functional phenotype of OA osteoblasts, was shown by modulating both PTGS2 expression and PGE2 prostaglandin production. However, the chronic effect of MALAT1-KD showed no noticeable effects on osteogenic differentiation activity, measured either by OPG production, ALP activity or the innate ability of osteoblasts to mineralise. In conclusion, the results of this thesis provide evidence that the lncRNA MALAT1 is associated with the inflammatory response in multiple cells of the OA joint, is highly expressed in both cartilage and subchondral bone tissue and in OA osteoblasts regulates inflammation by modulation of COX-2 prostaglandin production.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Inflammation and Ageing
Funders: Other
Other Funders: Fawzeyah AQ alnajjar, Partially funded by the Kuwait Foundation for The Advancment of Science
Subjects: R Medicine > RB Pathology


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