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.
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.
Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden , Budapester Str. 27, 01069 Dresden, Germany.
Sandra
S
Rother
Structural Bioinformatics, BIOTEC TU Dresden , Tatzberg 47-51, 01307 Dresden, Germany.
Sergey A
SA
Samsonov
Institute of Physiological Chemistry, Carl Gustav Carus Faculty of Medicine, TU Dresden , Fiedlerstraße 42, 01307 Dresden, Germany.
Ute
U
Hempel
Institute of Physiological Chemistry, Carl Gustav Carus Faculty of Medicine, TU Dresden , Fiedlerstraße 42, 01307 Dresden, Germany.
Sarah
S
Vogel
Biomaterials Department, INNOVENT e.V. , Prüssingstraße 27 B, 07745 Jena, Germany.
Stephanie
S
Moeller
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.
Joanna
J
Blaszkiewicz
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.
Sebastian
S
Köhling
Biomaterials Department, INNOVENT e.V. , Prüssingstraße 27 B, 07745 Jena, Germany.
Matthias
M
Schnabelrauch
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.
Jörg
J
Rademann
Structural Bioinformatics, BIOTEC TU Dresden , Tatzberg 47-51, 01307 Dresden, Germany.
M Teresa
MT
Pisabarro
Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden , Budapester Str. 27, 01069 Dresden, Germany.
Vera
V
Hintze
Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden , Budapester Str. 27, 01069 Dresden, Germany.
Dieter
D
Scharnweber
D002809:Chondroitin Sulfates / Q000008:administration & dosage / Q000737:chemistry; D004705:Endocytosis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006025:Glycosaminoglycans / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis* / Q000737:chemistry; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020349:Surface Plasmon Resonance; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis* / Q000737:chemistry; D014945:Wound Healing / Q000187:drug effects
D006025:Glycosaminoglycans; C514519:LDLR-related protein 1A, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D006820:Hyaluronic Acid; D002809:Chondroitin Sulfates