Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3)
Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibi...
| Glavni autori: | , , , , , , |
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| Format: | Journal article |
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American Society for Pharmacology and Experimental Therapeutics
2017
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| _version_ | 1826272186078330880 |
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| author | Chanalaris, A Doherty, C Marsden, B Bambridge, G Wren, S Nagase, H Troeberg, L |
| author_facet | Chanalaris, A Doherty, C Marsden, B Bambridge, G Wren, S Nagase, H Troeberg, L |
| author_sort | Chanalaris, A |
| collection | OXFORD |
| description | Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3), through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1). We discovered that suramin (C51H40N6O23S6) bound to TIMP-3 with a KD value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin with thrombospondin motifs 5 (ADAMTS-5). NF279, a structural analogue of suramin, has increased affinity for TIMP-3 and increased ability to inhibit TIMP- 3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis. |
| first_indexed | 2024-03-06T22:08:33Z |
| format | Journal article |
| id | oxford-uuid:5101fa35-425e-4f56-a481-45cf3cd33190 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T22:08:33Z |
| publishDate | 2017 |
| publisher | American Society for Pharmacology and Experimental Therapeutics |
| record_format | dspace |
| spelling | oxford-uuid:5101fa35-425e-4f56-a481-45cf3cd331902022-03-26T16:17:00ZSuramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3)Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5101fa35-425e-4f56-a481-45cf3cd33190Symplectic Elements at OxfordAmerican Society for Pharmacology and Experimental Therapeutics2017Chanalaris, ADoherty, CMarsden, BBambridge, GWren, SNagase, HTroeberg, LOsteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3), through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1). We discovered that suramin (C51H40N6O23S6) bound to TIMP-3 with a KD value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin with thrombospondin motifs 5 (ADAMTS-5). NF279, a structural analogue of suramin, has increased affinity for TIMP-3 and increased ability to inhibit TIMP- 3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis. |
| spellingShingle | Chanalaris, A Doherty, C Marsden, B Bambridge, G Wren, S Nagase, H Troeberg, L Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3) |
| title | Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3) |
| title_full | Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3) |
| title_fullStr | Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3) |
| title_full_unstemmed | Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3) |
| title_short | Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 (TIMP-3) |
| title_sort | suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3 timp 3 |
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