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

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 ( _RE GAG) with improved neutralizing properties for DKK1. In vitro and in vivo assays show that the GAG modification to obtain _RE GAG translated into increased WNT pathway activity and improved bone regeneration in a mouse calvaria defect model with critical size bone lesions. Importantly, the developed _RE GAG 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lorenz Hofbauer reports a relationship with Alexion that includes: funding grants. Lorenz Hofbauer reports a relationship with Ascendis Pharma, Inc. that includes: funding grants. Lorenz Hofbauer reports a relationship with Takeda Pharmaceutical Co Ltd that includes: funding grants. Lorenz Hofbauer reports a relationship with UCB Inc that includes: funding grants. Lorenz Hofbauer reports a relationship with Amgen Inc that includes: consulting or advisory. Lorenz Hofbauer reports a relationship with Pharmacosmos, Inc. that includes: consulting or advisory. Lorenz Hofbauer reports a relationship with UCB Inc that includes: consulting or advisory.
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