Rational engineering of glycosaminoglycan-based Dickkopf-1 scavengers to improve bone regeneration
Research output: Contribution to journal › Research article › Contributed › peer-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 language | English |
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Article number | 122105 |
Number of pages | 17 |
Journal | Biomaterials |
Volume | 297 |
Early online date | 31 Mar 2023 |
Publication status | Published - Jun 2023 |
Peer-reviewed | Yes |
External IDs
PubMed | 37031548 |
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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
ASJC Scopus subject areas
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