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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

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.

Details

Original languageEnglish
Pages (from-to)3252-3261
Number of pages10
JournalBiomacromolecules
Volume17
Issue number10
Publication statusPublished - 10 Oct 2016
Peer-reviewedYes

External IDs

Scopus 84991252864
ORCID /0000-0002-5611-9903/work/142244039

Keywords

Keywords

  • Chondroitin Sulfates/administration & dosage, Endocytosis/drug effects, Gene Expression Regulation/drug effects, Glycosaminoglycans/administration & dosage, Humans, Hyaluronic Acid/administration & dosage, Low Density Lipoprotein Receptor-Related Protein-1/biosynthesis, Mesenchymal Stem Cells/drug effects, Protein Binding/drug effects, Surface Plasmon Resonance, Tissue Inhibitor of Metalloproteinase-3/biosynthesis, Wound Healing/drug effects