Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases.
Degradation of the cartilage proteoglycan aggrecan is a key early event in the development of osteoarthritis. Adamalysin with thrombospondin motifs (ADAMTS) -4 and ADAMTS-5 are considered to be the main enzymes responsible for aggrecan breakdown, making them attractive drugs targets. Here we show th...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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2008
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| _version_ | 1797053452175540224 |
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| author | Troeberg, L Fushimi, K Khokha, R Emonard, H Ghosh, P Nagase, H |
| author_facet | Troeberg, L Fushimi, K Khokha, R Emonard, H Ghosh, P Nagase, H |
| author_sort | Troeberg, L |
| collection | OXFORD |
| description | Degradation of the cartilage proteoglycan aggrecan is a key early event in the development of osteoarthritis. Adamalysin with thrombospondin motifs (ADAMTS) -4 and ADAMTS-5 are considered to be the main enzymes responsible for aggrecan breakdown, making them attractive drugs targets. Here we show that calcium pentosan polysulfate (CaPPS), a chemically sulfated xylanopyranose from beechwood, is a multifaceted exosite inhibitor of the aggrecanases and protects cartilage against aggrecan degradation. CaPPS interacts with the noncatalytic spacer domain of ADAMTS-4 and the cysteine-rich domain of ADAMTS-5, blocking activity against their natural substrate aggrecan with inhibitory concentration 50 values of 10-40 nM but only weakly inhibiting hydrolysis of a nonglycosylated recombinant protein substrate. In addition, CaPPS increased cartilage levels of tissue inhibitor of metalloproteinases-3 (TIMP-3), an endogenous inhibitor of ADAMTS-4 and -5. This was due to the ability of CaPPS to block endocytosis of TIMP-3 mediated by low-density lipoprotein receptor-related protein. CaPPS also increased the affinity of TIMP-3 for ADAMTS-4 and -5 by more than 100-fold, improving the efficacy of TIMP-3 as an aggrecanase inhibitor. Studies with TIMP-3-null mouse cartilage indicated that CaPPS inhibition of aggrecan degradation is TIMP-3 dependent. These unique properties make CaPPS a prototypic disease-modifying agent for osteoarthritis. |
| first_indexed | 2024-03-06T18:43:57Z |
| format | Journal article |
| id | oxford-uuid:0dda8039-9e70-4af1-84ee-d361ac25def8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:43:57Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:0dda8039-9e70-4af1-84ee-d361ac25def82022-03-26T09:42:40ZCalcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0dda8039-9e70-4af1-84ee-d361ac25def8EnglishSymplectic Elements at Oxford2008Troeberg, LFushimi, KKhokha, REmonard, HGhosh, PNagase, HDegradation of the cartilage proteoglycan aggrecan is a key early event in the development of osteoarthritis. Adamalysin with thrombospondin motifs (ADAMTS) -4 and ADAMTS-5 are considered to be the main enzymes responsible for aggrecan breakdown, making them attractive drugs targets. Here we show that calcium pentosan polysulfate (CaPPS), a chemically sulfated xylanopyranose from beechwood, is a multifaceted exosite inhibitor of the aggrecanases and protects cartilage against aggrecan degradation. CaPPS interacts with the noncatalytic spacer domain of ADAMTS-4 and the cysteine-rich domain of ADAMTS-5, blocking activity against their natural substrate aggrecan with inhibitory concentration 50 values of 10-40 nM but only weakly inhibiting hydrolysis of a nonglycosylated recombinant protein substrate. In addition, CaPPS increased cartilage levels of tissue inhibitor of metalloproteinases-3 (TIMP-3), an endogenous inhibitor of ADAMTS-4 and -5. This was due to the ability of CaPPS to block endocytosis of TIMP-3 mediated by low-density lipoprotein receptor-related protein. CaPPS also increased the affinity of TIMP-3 for ADAMTS-4 and -5 by more than 100-fold, improving the efficacy of TIMP-3 as an aggrecanase inhibitor. Studies with TIMP-3-null mouse cartilage indicated that CaPPS inhibition of aggrecan degradation is TIMP-3 dependent. These unique properties make CaPPS a prototypic disease-modifying agent for osteoarthritis. |
| spellingShingle | Troeberg, L Fushimi, K Khokha, R Emonard, H Ghosh, P Nagase, H Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. |
| title | Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. |
| title_full | Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. |
| title_fullStr | Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. |
| title_full_unstemmed | Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. |
| title_short | Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. |
| title_sort | calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases |
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