Heparan Sulfate Proteoglycan Synthesis Is Dysregulated in Human Osteoarthritic Cartilage.

Chanalaris, Anastasios, Clarke, Hannah, Guimond, Scott E, Vincent, Tonia L, Turnbull, Jeremy E ORCID: 0000-0002-1791-754X and Troeberg, Linda (2019) Heparan Sulfate Proteoglycan Synthesis Is Dysregulated in Human Osteoarthritic Cartilage. The American journal of pathology, 189 (3). pp. 632-647.

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Abstract

Osteoarthritis (OA) is a common degenerative joint disease, characterized by cartilage loss and subchondral bone remodeling 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 extracellular signal-regulated kinase phosphorylation in response to fibroblast growth factor 2, showing that changes in 6-O-sulfation impact a key cartilage signaling 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
Uncontrolled Keywords:	Cartilage, Knee Joint, Chondrocytes, Humans, Osteoarthritis, Knee, Sulfotransferases, Fibroblast Growth Factor 2, MAP Kinase Signaling System, Gene Expression Regulation, Female, Male, Syndecan-4
Depositing User:	Symplectic Admin
Date Deposited:	06 Mar 2019 10:14
Last Modified:	19 Jan 2023 00:57
DOI:	10.1016/j.ajpath.2018.11.011
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3033848