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Title (Primary) Structural and functional insights into the interaction of sulfated glycosaminoglycans with tissue inhibitor of metalloproteinase-3 – A possible regulatory role on extracellular matrix homeostasis
Author Rother, S.; Samsonov, S.A.; Hofmann, T.; Blaszkiewicz, J.; Köhling, S.; Moeller, S.; Schnabelrauch, M.; Rademann, J.; Kalkhof, S.; von Bergen, M.; Pisabarro, M.T.; Scharnweber, D.; Hintze, V.;
Journal Acta Biomaterialia
Year 2016
Department MOLSYB;
Volume 45
Language englisch;
POF III (all) F11;
Keywords Tissue inhibitor of metalloproteinase-3; Glycosaminoglycans; Hyaluronan/sulfated hyaluronan; Matrix metalloproteinase; Molecular modeling; Chronic wound healing
UFZ wide themes RU3;
Abstract An imbalance between tissue-degrading matrix metalloproteinases (MMPs) and their counterparts’ tissue inhibitors of metalloproteinases (TIMPs) causes pathologic extracellular matrix (ECM) degradation in chronic wounds and requires new adaptive biomaterials that interact with these regulators to re-establish their balance. Sulfated glycosaminoglycans (GAGs) and TIMP-3 are key modulators of tissue formation and remodeling. However, little is known about their molecular interplay. GAG/TIMP-3 interactions were characterized combining surface plasmon resonance, ELISA, molecular modeling and hydrogen/deuterium exchange mass spectrometry. We demonstrate the potential of solute and surface-bound sulfated hyaluronan (sHA) and chondroitin sulfate (sCS) derivatives to manipulate GAG/TIMP-3 interactions by varying GAG concentration, sulfation degree and chain length. Three GAG binding sites in the N- and C-terminal domains of TIMP-3 were identified. We reveal no overlap with the matrix metalloproteinases (MMP)-binding site, elucidating why GAGs did not change MMP-1/-2 inhibition by TIMP-3 in enzyme kinetics. Since we prove that GAGs alone have a low impact on MMP activity, sHA and sCS offer a promising strategy to possibly control ECM remodeling via stabilizing and accumulating TIMP-3 by maintaining its MMP inhibitory activity under GAG-bound conditions. Whether GAG-based functional biomaterials can be applied to foster chronic wound healing by shifting the MMP/TIMP balance to a healing promoting state needs to be evaluated in vivo.
ID 18109
Persistent UFZ Identifier https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=18109
Rother, S., Samsonov, S.A., Hofmann, T., Blaszkiewicz, J., Köhling, S., Moeller, S., Schnabelrauch, M., Rademann, J., Kalkhof, S., von Bergen, M., Pisabarro, M.T., Scharnweber, D., Hintze, V. (2016):
Structural and functional insights into the interaction of sulfated glycosaminoglycans with tissue inhibitor of metalloproteinase-3 – A possible regulatory role on extracellular matrix homeostasis
Acta Biomater. 45 , 143 - 154