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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

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

OriginalspracheEnglisch
Aufsatznummer122105
Seitenumfang17
FachzeitschriftBiomaterials
Jahrgang297
Frühes Online-Datum31 März 2023
PublikationsstatusVeröffentlicht - Juni 2023
Peer-Review-StatusJa

Externe 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

Schlagworte

Schlagwörter

  • Bone healing, De novo rational design, Dickkopf-1, Glycosaminoglycans, Pharmacophore modeling, WNT signaling