Clusterin secretion is attenuated by the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α in models of cartilage degradation
Matta, Csaba; Fellows, Christopher R; Quasnichka, Helen; Williams, Adam; Jeremiasse, Bernadette; Allaway, David; Mobasheri, Ali
(2021) Journal of Orthopaedic Research, volume 39, issue 5, pp. 1017 - 1029
(Article)
Abstract
The protein clusterin has been implicated in the molecular alterations that occur in articular cartilage during osteoarthritis (OA). Clusterin exists in two isoforms with opposing functions, and their roles in cartilage have not been explored. The secreted form of clusterin (sCLU) is a cytoprotective extracellular chaperone that prevents protein aggregation,
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enhances cell proliferation and promotes viability, whereas nuclear clusterin acts as a pro-death signal. Therefore, these two clusterin isoforms may be putative molecular markers of repair and catabolic responses in cartilage and the ratio between them may be important. In this study, we focused on sCLU and used established, pathophysiologically relevant, in vitro models to understand its role in cytokine-stimulated cartilage degradation. The secretome of equine cartilage explants, osteochondral biopsies and isolated unpassaged chondrocytes was analyzed by western blotting for released sCLU, cartilage oligomeric protein (COMP) and matrix metalloproteinases (MMP) 3 and 13, following treatment with the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α. Release of sulfated glycosaminoglycans (sGAG) was determined using the dimethylmethylene blue assay. Clusterin messenger RNA (mRNA) expression was quantified by quantitative real-time polymerase chain reaction. MMP-3, MMP-13, COMP, and sGAG release from explants and osteochondral biopsies was elevated with cytokine treatment, confirming cartilage degradation in these models. sCLU release was attenuated with cytokine treatment in all models, potentially limiting its cytoprotective function. Clusterin mRNA expression was down-regulated 7-days post cytokine stimulation. These observations implicate sCLU in catabolic responses of chondrocytes, but further studies are required to evaluate its role in OA and its potential as an investigative biomarker.
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Keywords: apolipoprotein J, articular cartilage, biomarker, chondrocyte, clusterin, osteoarthritis (OA), proteomics, secretome, Orthopedics and Sports Medicine, Journal Article
ISSN: 0736-0266
Publisher: John Wiley and Sons Inc.
Note: Funding Information: Csaba Matta was supported by the European Commission through a Marie Skłodowska‐Curie Intra‐European Fellowship for career development (project number: 625746; acronym: CHONDRION; FP7‐PEOPLE‐2013‐IEF). Csaba Matta is supported by the Premium Postdoctoral Research Fellowship by the Hungarian Academy of Sciences, and a Bridging Fund from the Faculty of Medicine, University of Debrecen. The research was co‐financed by the Thematic Excellence Program of the Ministry for Innovation and Technology in Hungary, within the framework of the Space Sciences thematic program of the University of Debrecen (ED 18‐1‐2019‐0028). The research underpinning some of the work presented has received funding from a number of sources including The European Commission Framework 7 program (EU FP7; HEALTH.2012.2.4.5‐2, project number 305815; Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases, D‐BOARD) and the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115770, resources of which are composed of financial contribution from the European Union's Seventh Framework program (FP7/2007–2013) and EFPIA companies' in‐kind contribution. AM is a member of the Arthritis Research UK Center for Sport, Exercise, and Osteoarthritis, funded by Arthritis Research UK (grant reference number: 20194). AM is a member of the Applied Public‐Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium, a 5‐year project funded by the European Commission's Innovative Medicines Initiative (IMI). AM has received financial support from the European Structural and Social Funds through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the activity “Improvement of researchers” qualification by implementing world‐class R&D projects” of Measure No. 09.3.3‐LMT‐K‐712 (grant application code: 09.3.3‐LMT‐K‐712‐01‐0157, agreement No. DOTSUT‐215). AM has also received financial support from the European Structural and Social Funds through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the Program “Attracting Foreign Researchers for Research Implementation,” grant no. 0.2.2‐LMT‐K‐718‐02‐0022. Funding Information: Csaba Matta was supported by the European Commission through a Marie Sk?odowska-Curie Intra-European Fellowship for career development (project number: 625746; acronym: CHONDRION; FP7-PEOPLE-2013-IEF). Csaba Matta is supported by the Premium Postdoctoral Research Fellowship by the Hungarian Academy of Sciences, and a Bridging Fund from the Faculty of Medicine, University of Debrecen. The research was co-financed by the Thematic Excellence Program of the Ministry for Innovation and Technology in Hungary, within the framework of the Space Sciences thematic program of the University of Debrecen (ED 18-1-2019-0028). The research underpinning some of the work presented has received funding from a number of sources including The European Commission Framework 7 program (EU FP7; HEALTH.2012.2.4.5-2, project number 305815; Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases, D-BOARD) and the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115770, resources of which are composed of financial contribution from the European Union's Seventh Framework program (FP7/2007?2013) and EFPIA companies' in-kind contribution. AM is a member of the Arthritis Research UK Center for Sport, Exercise, and Osteoarthritis, funded by Arthritis Research UK (grant reference number: 20194). AM is a member of the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium, a 5-year project funded by the European Commission's Innovative Medicines Initiative (IMI). AM has received financial support from the European Structural and Social Funds through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the activity ?Improvement of researchers? qualification by implementing world-class R&D projects? of Measure No. 09.3.3-LMT-K-712 (grant application code: 09.3.3-LMT-K-712-01-0157, agreement No. DOTSUT-215). AM has also received financial support from the European Structural and Social Funds through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the Program ?Attracting Foreign Researchers for Research Implementation,? grant no. 0.2.2-LMT-K-718-02-0022. Publisher Copyright: © 2020 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.
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