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Biomacromolecules. 2016 Oct 10;17(10):3252-3261. Epub 2016 Sep 20.

Sulfated Hyaluronan Alters the Interaction Profile of TIMP-3 with the Endocytic Receptor LRP-1 Clusters II and IV and Increases the Extracellular TIMP-3 Level of Human Bone Marrow Stromal Cells.

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Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden , Budapester Str. 27, 01069 Dresden, Germany.
Structural Bioinformatics, BIOTEC TU Dresden , Tatzberg 47-51, 01307 Dresden, Germany.
Institute of Physiological Chemistry, Carl Gustav Carus Faculty of Medicine, TU Dresden , Fiedlerstraße 42, 01307 Dresden, Germany.
Biomaterials Department, INNOVENT e.V. , Prüssingstraße 27 B, 07745 Jena, Germany.
Institute of Pharmacy & Institute of Chemistry and Biochemistry, Freie Universität Berlin , Königin-Luise-Str. 2, 14195 Berlin, Germany.
Institute of Medical Physics and Biophysics, Universität Leipzig , Härtelstr. 16/18, 04107 Leipzig, Germany.


Sulfated glycosaminoglycans (sGAGs) modulate cellular processes via their interaction with extracellular matrix (ECM) proteins. We revealed a direct binding of tissue inhibitor of metalloproteinase-3 (TIMP-3) to the endocytic receptor low-density lipoprotein receptor-related protein (LRP-1) clusters II and IV using surface plasmon resonance. Sulfated hyaluronan (sHA) and chondroitin sulfate (sCS) derivatives interfered with TIMP-3/LRP-1 complex formation in a sulfation-dependent manner stronger than heparin. Electrostatic potential calculations suggested a competition between negatively charged GAGs and highly negatively charged complement-like domains of LRP-1 for the binding to a positively charged area of TIMP-3 as an underlying mechanism. In vitro studies revealed increased amounts of pericellular TIMP-3 in the presence of sHA as a consequence of the blocked protein uptake. GAG derivatives as part of biomaterials might post-translationally modulate TIMP-3 levels stronger than native GAGs, thus exhibiting catabolic effects on the ECM, which could prevent extensive pathological matrix degradation and promote wound healing.

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