Cecilie F Kjelgaard-Petersen1, Neha Sharma2, Ashref Kayed3, Morten A Karsdal4, Ali Mobasheri5, Per Hägglund6, Anne-Christine Bay-Jensen7, Christian S Thudium8. 1. Rheumatology, Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark; Department of Bioengineering and Biomedicine, Technical University of Denmark, Søltofts Plads Building 221, DK-2800 Kgs. Lyngby, Denmark. 2. Rheumatology, Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark; Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Electronic address: nes@nordicbio.com. 3. Rheumatology, Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. Electronic address: ask@nordicbio.com. 4. Rheumatology, Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. Electronic address: mk@nordicbio.com. 5. Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences University of Surrey, Guildford GU2 7AL, United Kingdom. Electronic address: a.mobasheri@surrey.ac.uk. 6. Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Electronic address: pmh@sund.ku.dk. 7. Rheumatology, Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. Electronic address: acbj@nordicbio.com. 8. Rheumatology, Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. Electronic address: cst@nordicbio.com.
Abstract
OBJECTIVE: Currently, there are no disease-modifying osteoarthritis drugs (DMOADs) approved for osteoarthritis. It is hypothesized that a subtype of OA may be driven by inflammation and may benefit from treatment with anti-inflammatory small molecule inhibitors adopted from treatments of rheumatoid arthritis. This study aimed to investigate how small molecule inhibitors of intracellular signaling modulate cartilage degradation and formation as a pre-clinical model for structural effects. DESIGN: Bovine cartilage explants were cultured with oncostatin M (OSM) and tumour necrosis factor α (TNF-α) either alone or combined with the small molecule inhibitors: SB203580 (p38 inhibitor), R406 (Spleen tyrosine kinase (Syk) inhibitor), TPCA-1 (Inhibitor of κB kinase (Ikk) inhibitor), or Tofacitinib (Tofa) (Janus kinases (Jak) inhibitor). Cartilage turnover was assessed with the biomarkers of degradation (AGNx1 and C2M), and type II collagen formation (PRO-C2) using ELISA. Explant proteoglycan content was assessed by Safranin O/Fast Green staining. RESULTS: R406, TPCA-1 and Tofa reduced the cytokine-induced proteoglycan loss and decreased AGNx1 release 3.7-, 43- and 32-fold, respectively. SB203580 showed no effect. All inhibitors suppressed C2M at a concentration of 3 µM. TPCA-1 and Tofa increased the cytokine reduced PRO-C2 3.5 and 3.7-fold, respectively. CONCLUSION: Using a pre-clinical model we found that the inhibitors TPCA-1 and Tofa inhibited cartilage degradation and rescue formation of type II collagen under inflammatory conditions, while R406 and SB203580 only inhibited cartilage degradation, and SB203580 only partially. These pre-clinical data suggest that TPCA-1 and Tofa preserve and help maintain cartilage ECM under inflammatory conditions and could be investigated further as DMOADs for inflammation-driven osteoarthritis.
OBJECTIVE: Currently, there are no disease-modifying osteoarthritis drugs (DMOADs) approved for osteoarthritis. It is hypothesized that a subtype of OA may be driven by inflammation and may benefit from treatment with anti-inflammatory small molecule inhibitors adopted from treatments of rheumatoid arthritis. This study aimed to investigate how small molecule inhibitors of intracellular signaling modulate cartilage degradation and formation as a pre-clinical model for structural effects. DESIGN:Bovine cartilage explants were cultured with oncostatin M (OSM) and tumour necrosis factor α (TNF-α) either alone or combined with the small molecule inhibitors: SB203580 (p38 inhibitor), R406 (Spleen tyrosine kinase (Syk) inhibitor), TPCA-1 (Inhibitor of κB kinase (Ikk) inhibitor), or Tofacitinib (Tofa) (Janus kinases (Jak) inhibitor). Cartilage turnover was assessed with the biomarkers of degradation (AGNx1 and C2M), and type II collagen formation (PRO-C2) using ELISA. Explant proteoglycan content was assessed by Safranin O/Fast Green staining. RESULTS: R406, TPCA-1 and Tofa reduced the cytokine-induced proteoglycan loss and decreased AGNx1 release 3.7-, 43- and 32-fold, respectively. SB203580 showed no effect. All inhibitors suppressed C2M at a concentration of 3 µM. TPCA-1 and Tofa increased the cytokine reduced PRO-C2 3.5 and 3.7-fold, respectively. CONCLUSION: Using a pre-clinical model we found that the inhibitors TPCA-1 and Tofa inhibited cartilage degradation and rescue formation of type II collagen under inflammatory conditions, while R406 and SB203580 only inhibited cartilage degradation, and SB203580 only partially. These pre-clinical data suggest that TPCA-1 and Tofa preserve and help maintain cartilage ECM under inflammatory conditions and could be investigated further as DMOADs for inflammation-driven osteoarthritis.
Authors: Meagan J Makarczyk; Qi Gao; Yuchen He; Zhong Li; Michael S Gold; Mark C Hochberg; Bruce A Bunnell; Rocky S Tuan; Stuart B Goodman; Hang Lin Journal: Tissue Eng Part C Methods Date: 2021-02-04 Impact factor: 3.056
Authors: Nathalie G M Thielen; Margot Neefjes; Elly L Vitters; Henk M van Beuningen; Arjen B Blom; Marije I Koenders; Peter L E M van Lent; Fons A J van de Loo; Esmeralda N Blaney Davidson; Arjan P M van Caam; Peter M van der Kraan Journal: Cells Date: 2022-04-05 Impact factor: 6.600
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