Rational engineering of glycosaminoglycan-based Dickkopf-1 scavengers to improve bone regeneration

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

The WNT signaling pathway is a central regulator of bone development and regeneration. Functional alterations of WNT ligands and inhibitors are associated with a variety of bone diseases that affect bone fragility and result in a high medical and socioeconomic burden. Hence, this cellular pathway has emerged as a novel target for bone-protective therapies, e.g. in osteoporosis. Here, we investigated glycosaminoglycan (GAG) recognition by Dickkopf-1 (DKK1), a potent endogenous WNT inhibitor, and the underlying functional implications in order to develop WNT signaling regulators. In a multidisciplinary approach we applied in silico structure-based de novo design strategies and molecular dynamics simulations combined with synthetic chemistry and surface plasmon resonance spectroscopy to Rationally Engineer oligomeric Glycosaminoglycan derivatives (REGAG) with improved neutralizing properties for DKK1. In vitro and in vivo assays show that the GAG modification to obtain REGAG translated into increased WNT pathway activity and improved bone regeneration in a mouse calvaria defect model with critical size bone lesions. Importantly, the developed REGAG outperformed polymeric high-sulfated hyaluronan (sHA3) in enhancing bone healing up to 50% due to their improved DKK1 binding properties. Thus, rationally engineered GAG variants may represent an innovative strategy to develop novel therapeutic approaches for regenerative medicine.

Details

Original languageEnglish
Article number122105
Number of pages17
JournalBiomaterials
Volume297
Early online date31 Mar 2023
Publication statusPublished - Jun 2023
Peer-reviewedYes

External IDs

PubMed 37031548
unpaywall 10.1016/j.biomaterials.2023.122105
WOS 000980778000001
ORCID /0000-0002-8691-8423/work/142236074
ORCID /0000-0002-5611-9903/work/142244050
ORCID /0000-0001-7097-9953/work/142255939

Keywords

Keywords

  • Bone healing, De novo rational design, Dickkopf-1, Glycosaminoglycans, Pharmacophore modeling, WNT signaling, Bone Diseases, Bone and Bones/metabolism, Intercellular Signaling Peptides and Proteins, Bone Regeneration, Animals, Glycosaminoglycans/metabolism, Mice, Wnt Signaling Pathway