Dr. Gloria Ruiz-Gómez (Dresden, DE), Dr. Juliane Salbach-Hirsch (Dresden, DE), Dr. Jan-Niklas Dürig (Berlin, DE), Dr. Linda Köhler (Dresden, DE), Kanagasabai Balamurugan (Dresden, DE), Sandra Rother (Dresden, DE), Sophie-Luise Heidig (Dresden, DE), Dr. Stephanie Moeller (Jena, DE), Dr. Matthias Schnabelrauch (Jena, DE), Giulia Furesi (Dresden, DE), Sophie Pählig (Dresden, DE), Pedro Guillem-Gloria (Dresden, DE), Christine Hofbauer (Dresden, DE), Professor M. Teresa Pisabarro (Dresden, DE), Professor Jörg Rademann (Berlin, DE), Professor Lorenz Hofbauer (Dresden, DE), Dr. Vera Hintze (Dresden, DE)
Abstract text (incl. figure legends and references)
Introduction: The WNT signaling pathway is a key regulator of bone development and regeneration comprising ligands, receptor and inhibitors. Functional alterations of WNT ligands and inhibitors are linked to bone diseases affecting bone fragility and resulting 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 [1, 2]. Antibodies have been successful for neutralizing inhibitors but their application is limited due to potential cardiovascular risk [3].
Objectives: The aim was to investigate glycosaminoglycan (GAG) recognition by Dickkopf-1 (DKK1), a potent endogenous WNT inhibitor, and the underlying functional implications to develop novel WNT signaling regulators [4].
Materials and methods: In an interdisciplinary approach we combined in silico structure-based de novo design strategies and molecular dynamics simulations with synthetic chemistry and surface plasmon resonance spectroscopy to rationally engineer oligomeric GAG derivatives (REGAG) with improved neutralizing properties for DKK1. These molecules were validated in vitro in a Wnt-responsive cell line and in vivo in a mouse calvaria defect model with critical size bone lesions after absorbing to gelatin sponges [4].
Results: In vitro Alpl gene expression, Wnt reporter assay and in vivo analyses showed that the REGAGs modification translated into increased WNT pathway activity and improved bone regeneration. Importantly, REGAG outperformed polymeric high-sulfated hyaluronan, in enhancing bone healing due to improved DKK1 scavenging properties [4].
Conclusion: REGAG may represent an innovative strategy to develop novel therapeutic approaches for regenerative medicine [4].
[1] Saag KG et al. 2017, N Engl J Med., 377(15):1417-1427
[2] Florio M et al. 2016, Nat Commun. 7:11505.
[3] Chames P et al. 2009, Br J Pharmacol. 157(2):220-33.
[4] Ruiz-Gomez G et al. 2023, Biomaterials 297, 122105