Article Text
Abstract
Objectives Suramin is an old drug used for the treatment of African sleeping sickness. We investigated therapeutic repositioning of suramin to protect against cartilage damage, as suramin may interact with tissue inhibitor of metalloproteinase-3 (TIMP3).
Methods In vitro extracellular matrix (ECM) accumulation and turnover in the presence or absence of suramin were studied in the ATDC5 micromass model of chondrogenesis and in pellet cultures of human articular chondrocytes from osteoarthritis and control patients, by gene expression, protein analysis, colorimetric staining, immunoprecipitation, fluorimetric analysis and immunohistochemistry. To study suramin in vivo, the drug was injected intra-articularly in the papain model of joint damage. Disease severity was analysed by histology, immunohistochemistry and contrast-enhanced nanofocus CT.
Results In ATDC5 micromasses, suramin increased TIMP3 levels and decreased the activity of matrix metalloproteinases (MMPs) and aggrecanases. Suramin treatment resulted in increased glycosaminoglycans. This effect on the ECM was blocked by an anti-TIMP3 antibody. Direct interaction between suramin and endogenous TIMP3 was demonstrated in immunoprecipitates. Mice treated intra-articularly with suramin injections showed reduced cartilage damage compared with 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 loss of articular cartilage in a mouse model of cartilage damage. The effects appear to be mediated by a functional increase of TIMP3 and a subsequent decrease in the activity of catabolic enzymes. Thus, suramin repositioning could be considered to prevent progressive cartilage damage and avoid evolution toward osteoarthritis.
- osteoarthritis
- chondrocytes
- treatment
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Statistics from Altmetric.com
Footnotes
Contributors All authors contributed to the planning of the study, the design of the experiments and the analysis of the data. LAG, MK and JVD performed experiments. SM, GK, GO, RJL and FC supervised experiments. LAG, SM, RJL and FC wrote the manuscript. All authors provided input and suggestions and approved the final version of text.
Funding This work was supported by grant G.0A06.13 from the Flanders Research Foundation (FWO Vlaanderen). SM and FC were the recipients of Marie-Curie IEF Fellowships. The nano-CT images have been generated on the X-ray CT facility of the Department of Development and Regeneration of the KU Leuven, financed by the Hercules Foundation (project AKUL/13/47: Nano CT and Bioreactor CT for a better understanding of the dynamics of 3D tissue formation in regenerative medicine: from clustered cells toward organised multi-tissue system and whole organs).
Competing interests None declared.
Ethics approval UZ Leuven Ethical Committee.
Provenance and peer review Not commissioned; externally peer reviewed.