Heparan Sulfate Proteoglycan Synthesis is Dysregulated in Human Osteoarthritic Cartilage

Chanalaris, Anastasios, Clarke, Hannah, Guimond, Scott E, Vincent, Tonia L, Turnbull, Jeremy E and Troeberg, Linda (2019) Heparan Sulfate Proteoglycan Synthesis is Dysregulated in Human Osteoarthritic Cartilage. American Journal of Pathology, 189 (3). pp. 632-647. ISSN 0002-9440

[img] PDF (Accepted_Manuscript) - Submitted Version
Restricted to Repository staff only until 13 December 2019.
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (2525kB) | Request a copy

    Abstract

    Osteoarthritis (OA) is a common degenerative joint disease, characterized by cartilage loss and subchondral bone remodelling in response to abnormal mechanical load. Heparan sulfate (HS) proteoglycans bind to many proteins that regulate cartilage homeostasis, including growth factors, morphogens, proteases, and their inhibitors, and modulate their localization, retention, and biological activity. Changes in HS expression and structure may thus have important consequences for joint health. We analyzed normal and osteoarthritic human knee cartilage, and found HS biosynthesis was markedly disrupted in OA, with 45% of the 38 genes analyzed differentially regulated in diseased cartilage. The expression of several HS core proteins, biosynthesis, and modification enzymes was increased in OA cartilage, whereas the expression of the HS proteoglycans syndecan 4 and betaglycan was reduced. The structure of HS was also altered, with increased levels of 6-O-sulfation in osteoarthritic samples, which correlated with increased expression of HS6ST1, a 6-O-sulfotransferase, and GLCE, an epimerase that promotes 6-O-sulfation. siRNA silencing of HS6ST1 expression in primary OA chondrocytes inhibited ERK phosphorylation in response to FGF2, showing that changes in 6-O-sulfation impact a key cartilage signalling pathway. Given the broad range of homeostatic and repair pathways that HS regulates, these changes in proteoglycan expression and HS structure are likely to have significant effects on joint health and progression of OA.

    Item Type: Article
    Additional Information: Copyright © 2018. Published by Elsevier Inc.
    Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
    Depositing User: LivePure Connector
    Date Deposited: 04 Jan 2019 16:30
    Last Modified: 11 Apr 2019 16:01
    URI: https://ueaeprints.uea.ac.uk/id/eprint/69450
    DOI: 10.1016/j.ajpath.2018.11.011

    Actions (login required)

    View Item