Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Drug repositioning is a recent pharmaceutical strategy to discover new uses for market-approved drugs with known safety profiles that can provide quick transition from the laboratory bench to bedside. Suramin is a poly-sulfonated molecule, used for the treatment of African sleeping sickness. Suramin has been used in vitro to isolate MMPs and tissue inhibitor of metalloproteinase 3 (TIMP3) from the rat uterus. Here, we investigated therapeutic repositioning of suramin to protect the joint against the development of osteoarthritis, hypothesizing that suramin interacts with cartilage extracellular matrix (ECM) proteins.
Methods: In vitro ECM deposition in the presence or absence of suramin was studied in murine chondrogenic ATDC5 cells or in human articular chondrocytes from osteoarthritis and control patients, by gene expression and protein analysis, colorimetric staining and immunohistochemistry. To study the effect of suramin in vivo, the drug was injected intra-articularly in the papain-model of osteoarthritis in wild-type C57/Bl6 mice. Disease severity was analyzed by histology, immunohistochemistry and contrast-enhanced nanofocus computed tomography.
Results: In ATDC5 micromass cultures, suramin treatment increased tissue inhibitor of metalloproteinase-3 (TIMP3) levels and decreased the activity of matrix metalloproteinases (MMPs) and aggrecanases. Suramin treatment thus resulted in increased glycosaminoglycan content. This effect on the cartilage ECM was prevented by co-culture with anti-TIMP3 antibody. Mice treated intra-articularly with repetitive suramin injections in the disease model of osteoarthritis, showed reduced cartilage damage compared to controls, with increased TIMP3, and decreased MMP and aggrecanase activity. Translational validation in human chondrocytes confirmed increased TIMP3 function and reduced cartilage breakdown after suramin treatment.
Conclusion: Suramin prevented the development of osteoarthritis in a mouse model of direct cartilage damage. Mechanistically, the effects of suramin appear to be mediated by a functional increase of TIMP3, and a subsequent decrease in the activity of catabolic enzymes.
To cite this abstract in AMA style:Guns LA, Monteagudo S, Kvasnytsia M, Kerckhofs G, Vandooren J, Opdenakker G, Cailotto F, Lories R. Repositioning Suramin As a Cartilage-Protective Drug [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/repositioning-suramin-as-a-cartilage-protective-drug/. Accessed September 25, 2021.
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