Biomaterials 2015-10-01

Structural and functional insights into sclerostin-glycosaminoglycan interactions in bone.

Juliane Salbach-Hirsch, Sergey A Samsonov, Vera Hintze, Christine Hofbauer, Ann-Kristin Picke, Martina Rauner, Jan-Philip Gehrcke, Stephanie Moeller, Matthias Schnabelrauch, Dieter Scharnweber, M Teresa Pisabarro, Lorenz C Hofbauer

Index: Biomaterials 67 , 335-45, (2015)

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Abstract

In order to improve bone defect regeneration, the development of new adaptive biomaterials and their functional and biological validation is warranted. Glycosaminoglycans (GAGs) are important extracellular matrix (ECM) components in bone and may display osteogenic properties that are potentially useful for biomaterial coatings. Using hyaluronan (HA), chondroitin sulfate (CS) and chemically modified highly sulfated HA and CS derivatives (sHA3 and sCS3; degree of sulfation ∼3), we evaluated how GAG sulfation modulates Wnt signaling, a major regulator of osteoblast, osteoclast and osteocyte biology. GAGs were tested for their capability to bind to sclerostin, an inhibitor of Wnt signaling, using surface plasmon resonance and molecular modeling to characterize their interactions. GAGs bound sclerostin in a concentration- and sulfate-dependent manner at a common binding region. These findings were confirmed in an LRP5/sclerostin interaction study and an in vitro model of Wnt activation. Here, pre-incubation of sclerostin with different GAGs led to a sulfate- and dose-dependent loss of its bioactivity. Using GAG-biotin derivatives in a competitive ELISA approach sclerostin was shown to be the preferred binding partner over Wnt3a. In conclusion, highly sulfated GAGs might control bone homeostasis via interference with sclerostin/LRP5/6 complex formation. Whether these properties can be utilized to improve bone regeneration needs to be validated in vivo. Copyright © 2015 Elsevier Ltd. All rights reserved.