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SAT0044 CCN4/WISP-1 Induces Reactive Oxygen Species Production in Osteoarthritic Synovial Fibroblasts
  1. C. Premat1,
  2. C. Chereau2,
  3. M. Corvol3,
  4. C. Chauvet4,
  5. F. Rannou3,
  6. D. Borderie3
  1. 1Inserm U1124
  2. 2Inserm U1016, Institut Cochin
  3. 3Inserm U1124
  4. 4Inserm 1124, Université Paris Descartes, Paris, France


Background Osteoarthritis (OA) is the most common degenerative joint disease characterised by slow progressive articular cartilage degradation, subchondral bone alteration and secondary synovial inflammation (1). The etiology of OA is not well understood. Recent studies have shown that CCN4/Wisp-1, a protein member of CCN family is implicated in OA (2). Indeed, CCN4 is overexpressed in OA synovial fibroblasts (OASFs) and increases IL6 production in these cells (3), suggesting CCN4 involvement in synovium inflammation during OA. Currently, nothing is known about any CCN4 implication in the oxidative stress during OA.

Objectives The purpose of this study was to evaluate the effects of CCN4 in the production of Reactive Oxygen Species (ROS) and antioxidant defenses (GSH,Trx/TXNIP, Thiols) in Human osteoarthritic synovial fibroblasts (hOASFs) in vitro.

Methods Samples of hOASFs were obtained from knee replacement surgery of four OA patients. Cells were incubated during 24 hours at 37°C, 5% CO2 with different concentrations of CCN4, between 0.1 to 1 μg/ml.

Hydrogen peroxide (H2O2), superoxide anion (O2.–) and nitric oxide (NO) were measured using fluorescent probes. The antioxidant status was evaluated by the determination of intracellular glutathione (GSH), thioredoxin (Trx), and thiols.

Results CCN4 increased hydrogen peroxide production in a dose dependent manner with maximum effect of 58% over control values at 1 μg/ml (p<0.01). CNN4 also increased superoxide anion production of 67% at 1 μg/ml (p<0.01). No effect of CCN4 was observed on NO production and intracellular concentrations of glutathione, thioredoxin and thiols were not modified by CCN4, whatever the concentrations.

Conclusions This study strongly suggests that CCN4 is implicated in ROS production by OA synovial cells. Oxidative stress doesn't stimulate antioxidant defenses.

Antioxidant proteins have inhibitory proteins, such as thioredoxin-interacting protein (TXNIP) (4). It mays intervene in this pathway and regulate thioredoxin activity. The relationship between CCN4, oxidative stress and inflammation should be more investigated during OA.


  1. Ashford S, Williard J. Osteoarthritis: A review. Nurse Pract. 12 mai 2014;39(5):1-8.

  2. Blom AB, van Lent PL, van der Kraan PM, van den Berg WB. To seek shelter from the WNT in osteoarthritis? WNT-signaling as a target for osteoarthritis therapy. Curr Drug Targets. mai 2010;11(5):620-9.

  3. Hou C-H, Tang C-H, Hsu C-J, Hou S-M, Liu J-F. CCN4 induces IL-6 production through αvβ5 receptor, PI3K, Akt, and NF-κB singling pathway in human synovial fibroblasts. Arthritis Res Ther. 23 janv 2013;15(1):R19.

  4. Abderrazak A, Syrovets T, Couchie D, El Hadri K, Friguet B, Simmet T, et al. NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol. 14 janv 2015;4C:296-307.

Disclosure of Interest None declared

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