C Steen-Louws1, J Popov-Celeketic2, S C Mastbergen3, K Coeleveld4, C E Hack5, N Eijkelkamp6, M Tryfonidou7, S Spruijt8, J A G van Roon9, F P J G Lafeber10. 1. Laboratory of Translational Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: C.Louws@umcutrecht.nl. 2. Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: J.Popov-Celeketic@umcutrecht.nl. 3. Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: S.Mastbergen@umcutrecht.nl. 4. Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: K.Coeleveld@umcutrecht.nl. 5. Laboratory of Translational Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: C.E.Hack@umcutrecht.nl. 6. Laboratory of Translational Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands; Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: N.Eijkelkamp@umcutrecht.nl. 7. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, University Utrecht, The Netherlands. Electronic address: M.A.Tryfonidou@uu.nl. 8. St. Maartens Hospital, The Netherlands. Electronic address: S.Spruijt@hagaziekenhuis.nl. 9. Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: J.vanRoon@umcutrecht.nl. 10. Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, University Utrecht, The Netherlands. Electronic address: f.lafeber@umcutrecht.nl.
Abstract
OBJECTIVE: Effective disease-modifying drugs for osteoarthritis (DMOAD) should preferably have chondroprotective, anti-inflammatory, and analgesic activity combined in a single molecule. We developed a fusion protein of IL4 and IL10 (IL4-10 FP), in which the biological activity of both cytokines is preserved. The present study evaluates the chondroprotective, anti-inflammatory, and analgesic activity of IL4-10 FP in in vitro and in vivo models of osteoarthritis. METHODS: Human osteoarthritic cartilage tissue and synovial tissue were cultured with IL4-10 FP. Cartilage proteoglycan turnover and release of pro-inflammatory, catabolic, and pain mediators by cartilage and synovial tissue were measured. The analgesic effect of intra-articularly injected IL4-10 FP was evaluated in a canine model of osteoarthritis by force-plate analysis. RESULTS: IL4-10 FP increased synthesis (P = 0.018) and decreased release (P = 0.018) of proteoglycans by osteoarthritic cartilage. Release of pro-inflammatory IL6 and IL8 by cartilage and synovial tissue was reduced in the presence of IL4-10 FP (all P < 0.05). The release of MMP3 by osteoarthritic cartilage and synovial tissue was decreased (P = 0.018 and 0.028) whereas TIMP1 production was not significantly changed. Furthermore, IL4-10 FP protected cartilage against destructive properties of synovial tissue mediators shown by the increased cartilage proteoglycan synthesis (P = 0.0235) and reduced proteoglycan release (P = 0.0163). Finally, intra-articular injection of IL4-10 FP improved the deficient joint loading in dogs with experimentally induced osteoarthritis. CONCLUSION: The results of current preliminary study suggest that IL4-10 FP has DMOAD potentials since it shows chondroprotective and anti-inflammatory effects in vitro, as well as potentially analgesic effect in a canine in vivo model of osteoarthritis.
OBJECTIVE: Effective disease-modifying drugs for osteoarthritis (DMOAD) should preferably have chondroprotective, anti-inflammatory, and analgesic activity combined in a single molecule. We developed a fusion protein of IL4 and IL10 (IL4-10 FP), in which the biological activity of both cytokines is preserved. The present study evaluates the chondroprotective, anti-inflammatory, and analgesic activity of IL4-10 FP in in vitro and in vivo models of osteoarthritis. METHODS:Humanosteoarthritic cartilage tissue and synovial tissue were cultured with IL4-10 FP. Cartilage proteoglycan turnover and release of pro-inflammatory, catabolic, and pain mediators by cartilage and synovial tissue were measured. The analgesic effect of intra-articularly injected IL4-10 FP was evaluated in a canine model of osteoarthritis by force-plate analysis. RESULTS:IL4-10 FP increased synthesis (P = 0.018) and decreased release (P = 0.018) of proteoglycans by osteoarthritic cartilage. Release of pro-inflammatory IL6 and IL8 by cartilage and synovial tissue was reduced in the presence of IL4-10 FP (all P < 0.05). The release of MMP3 by osteoarthritic cartilage and synovial tissue was decreased (P = 0.018 and 0.028) whereas TIMP1 production was not significantly changed. Furthermore, IL4-10 FP protected cartilage against destructive properties of synovial tissue mediators shown by the increased cartilage proteoglycan synthesis (P = 0.0235) and reduced proteoglycan release (P = 0.0163). Finally, intra-articular injection of IL4-10 FP improved the deficient joint loading in dogs with experimentally induced osteoarthritis. CONCLUSION: The results of current preliminary study suggest that IL4-10 FP has DMOAD potentials since it shows chondroprotective and anti-inflammatory effects in vitro, as well as potentially analgesic effect in a canine in vivo model of osteoarthritis.
Authors: Ramin Raoof; Christian Martin Gil; Floris P J G Lafeber; Huub de Visser; Judith Prado; Sabine Versteeg; Mirte N Pascha; Anne L P Heinemans; Youri Adolfs; Jeroen Pasterkamp; John N Wood; Simon C Mastbergen; Niels Eijkelkamp Journal: J Neurosci Date: 2021-08-16 Impact factor: 6.167
Authors: Cristine Steen-Louws; Peter Boross; Judith Prado; Jan Meeldijk; Jurgen B Langenhorst; Alwin D R Huitema; Marcel T den Hartog; Louis Boon; Floris P J G Lafeber; C Erik Hack; Niels Eijkelkamp; Jelena Popov-Celeketic Journal: Pharm Res Date: 2019-12-26 Impact factor: 4.200
Authors: Judith Prado; Remco H S Westerink; Jelena Popov-Celeketic; Cristine Steen-Louws; Aridaman Pandit; Sabine Versteeg; Wouter van de Worp; Deon H A J Kanters; Kris A Reedquist; Leo Koenderman; C Erik Hack; Niels Eijkelkamp Journal: Proc Natl Acad Sci U S A Date: 2021-03-16 Impact factor: 11.205
Authors: C Steen-Louws; S A Y Hartgring; J Popov-Celeketic; A P Lopes; M B M de Smet; N Eijkelkamp; F P J G Lafeber; C E Hack; J A G van Roon Journal: Clin Exp Immunol Date: 2018-11-11 Impact factor: 4.330
Authors: Michelle Teunissen; Alberto Miranda Bedate; Katja Coeleveld; Frank M Riemers; Björn P Meij; Floris P J G Lafeber; Marianna A Tryfonidou; Simon C Mastbergen Journal: Cartilage Date: 2021-05-20 Impact factor: 4.634
Authors: E M van Helvoort; H M de Visser; F P J G Lafeber; K Coeleveld; S Versteeg; H H Weinans; J Popov-Celeketic; N Eijkelkamp; S C Mastbergen Journal: Cartilage Date: 2021-06-23 Impact factor: 4.634