Building bone with bioinspired molecules

With advancing age, the human body´s natural capacity to consistently renew bones and maintain their resilience diminishes. This decline is enhanced by conditions like osteoporosis. This poses a significant health concern for the elderly and is becoming a growing economic challenge on society. In an effort to address this problem, scientists are actively seeking novel therapeutic strategies to enhance bone regeneration.

 

Building bone with bioinspired molecules

By employing computer models and simulations, a Dresden-based team created innovative bio-inspired compounds that enhance bone regeneration in mice. These compounds can be incorporated into biomaterials, allowing for their localized introduction into bone defects. These newly developed molecules derive from glycosaminoglycans, which are extended sugar chains like hyaluronic acid or heparin. These molecules could be used to turn-off proteins like DKK-1 and Sclerostin that block bone regeneration that could lead to new and more effective therapies for bone diseases.

DKK-1 and SCLEROSTIN are two important proteins that play significant roles in regulating bone health and development.

DKK-1 (Dickkopf-1) acts as an inhibitor of the Wnt signaling pathway. This pathway is crucial for bone formation. Overexpression of DKK-1 leads to a decrease in bone formation characterized by conditions with impaired bone density and increased fragility, such as osteoporosis.

SCLEROSTIN (SOST) is a Wnt signaling inhibitor and a negative regulator of bone formation. Sclerostin is primarily produced by osteocytes, which are bone cells embedded within the bone matrix.

Sclerostin and DKK-1 can be measured in human serum samples with an ELISA assay.

 

Biomedica´s DKK-1 ELISA assay (cat. no. BI-20413)

• 20µl sample volume
• Widely cited
• No sample dilution
• Fully validated

 

Biomedica´s Sclerostin ELISA assay (cat. no. 20492)

• The internationally most referenced Sclerostin ELISA!
• Rigorously validated according to FDA/ICH/EMEA guidelines
• 20µl sample volume

 

also available: Bioactive Sclerostin ELISA (cat. no. BI-20472)

Rational engineering of glycosaminoglycan-based Dickkopf-1 scavengers to improve bone regeneration. Ruiz-Gómez G, Salbach-Hirsch J, Dürig JN, Köhler L, Balamurugan K, Rother S, Heidig SL, Moeller S, Schnabelrauch M, Furesi G, Pählig S, Guillem-Gloria PM, Hofbauer C, Hintze V, Pisabarro MT, Rademann J, Hofbauer LC. Biomaterials. 2023 Jun;297:122105. doi: 10.1016/j.biomaterials.2023.122105. Epub 2023 Mar 31. PMID: 37031548.

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