title: Optimized alkylated cyclodextrin polysulphates with reduced risks on thromboembolic accidents improve osteoarthritic chondrocyte metabolism.
abstract: OBJECTIVE
  To compare the ability of different cyclodextrin polysulphate (CDPS) derivatives to affect human articular cartilage cell metabolism in vitro.
  
  
  METHODS
  OA chondrocytes were cultured in alginate and exposed to 5 µg/ml of 2,3,6-tri-O-methyl-β-cyclodextrin (ME-CD), 2,3-di-O-methyl-6-sulphate-β-cyclodextrin (ME-CD-6-S), 2,6-di-O-methyl-3-sulphate-β-cyclodextrin (ME-CD-3-S), (2-carboxyethyl)-β-CDPS (CE-CDPS), (2-hydroxypropyl)-β-CDPS (HP-CDPS), 6-monoamino-6-monodeoxy-β-CDPS (MA-CDPS) or β-CDPS for 5 days. Effects on IL-1-driven chondrocyte extracellular matrix (ECM) metabolism were assayed by analysis of the accumulation of aggrecan in the interterritorial matrix, IL-6 secretion and qPCR. MA-CDPS, HP-CDPS, CE-CDPS and CDPS were analysed for their in vitro effect on coagulation and their ability to activate platelets in an in vitro assay to detect possible cross-reactivity with heparin-induced thrombocytopenia (HIT) antibodies.
  
  
  RESULTS
  The monosulphated cyclodextrins ME-CD-6-S and -3-S failed to affect aggrecan synthesis and IL-6 secretion by the OA chondrocytes. Polysulphated cyclodextrins MA-CDPS, HP-CDPS, CE-CDPS and CDPS at 5 µg/ml concentrations, on the other hand, significantly induced aggrecan production and repressed IL-6 release by the chondrocytes in culture. aPTT and PT for all derivatives were lengthened for polysaccharide concentrations >50 µg/ml. Five micrograms per millilitre of β-CDPS concentrations that significantly modulated ECM ground substance production in vitro did not affect aPTT or PT. Furthermore, CE-CDPS, in contrast to MA-CDPS, HP-CDPS and CDPS, did not significantly activate platelets, suggesting a minimal potential to induce HIT thromboembolic accidents in vivo.
  
  
  CONCLUSIONS
  CE-CDPS is a new, structurally adjusted, sulphated β-cyclodextrin derivative with preserved chondroprotective capacity and a promising safety profile.
authors.affiliation: Department of Rheumatology, Laboratory of Connective Tissue Biology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Groeneboer
authors.forename: Stijn
authors.initials: S
authors.lastname: Lambrecht
authors.forename: Aad
authors.initials: A
authors.lastname: Dhollander
authors.forename: Peggy
authors.initials: P
authors.lastname: Jacques
authors.forename: Bert
authors.initials: B
authors.lastname: Vander Cruyssen
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Lories
authors.forename: Katrien
authors.initials: K
authors.lastname: Devreese
authors.forename: Koen
authors.initials: K
authors.lastname: Chiers
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.forename: Gust
authors.initials: G
authors.lastname: Verbruggen
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism*; D003470:Culture Media; D006801:Humans; D066298:In Vitro Techniques; D015539:Platelet Activation / Q000187:drug effects*; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013923:Thromboembolism / Q000517:prevention & control*; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D003470:Culture Media; D047392:beta-Cyclodextrins