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

Biomacromolecules. 2016 Oct 10;17(10):3252-3261. doi: 10.1021/acs.biomac.6b00980. Epub 2016 Sep 20.


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.

MeSH terms

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


  • Glycosaminoglycans
  • LDLR-related protein 1A, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • Hyaluronic Acid
  • Chondroitin Sulfates