Structural and functional insights into sclerostin-glycosaminoglycan interactions in bone

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

doi:10.1016/j.biomaterials.2015.07.021

Cited by 41 publications

(33 citation statements)

References 25 publications

(32 reference statements)

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“…Structural studies of sclerostin revealed the presence of a heparin-binding patch, which is formed from a linear region of positively charged amino acids in loops 2 and 3, which covers one side of the protein and promotes a functional association between sclerostin and heparin that localises sclerostin to the surface of transfected cells (Veverka et al 2009). More recently, this area was identified as a common binding region for various sulphated glycosaminoglycans (GAGs), which interfere with the interaction between sclerostin and LRP5/6 and restore WNT signalling in a reporter cell line (Salbach-Hirsch et al 2015). GAGs are long unbranched polysaccharide molecules that are present as heparan sulphate proteoglycans within the extracellular matrix of bone.…”

Section: Interactions With Cell-surface Receptors and Glycosaminoglycansmentioning

confidence: 99%

Novel actions of sclerostin on bone

Holdsworth

Roberts

2019

Journal of Molecular Endocrinology

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The discovery that two rare autosomal recessive high bone mass conditions were caused by the loss of sclerostin expression prompted studies into its role in bone homeostasis. In this article, we aim to bring together the wealth of information relating to sclerostin in bone though discussion of rare human disorders in which sclerostin is reduced or absent, sclerostin manipulation via genetic approaches and treatment with antibodies that neutralise sclerostin in animal models and in human. Together, these findings demonstrate the importance of sclerostin as a regulator of bone homeostasis and provide valuable insights into its biological mechanism of action. We summarise the current state of knowledge in the field, including the current understanding of the direct effects of sclerostin on the canonical WNT signalling pathway and the actions of sclerostin as an inhibitor of bone formation. We review the effects of sclerostin, and its inhibition, on bone at the cellular and tissue level and discuss new findings that suggest that sclerostin may also regulate adipose tissue. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of sclerostin.

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Section: Interactions With Cell-surface Receptors and Glycosaminoglycansmentioning

confidence: 99%

Novel actions of sclerostin on bone

Holdsworth

Roberts

2019

Journal of Molecular Endocrinology

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“…[180] In a similar approach, Hofbauer and co-workers utilized selectively sulfated HA and modified CS to analyze the impact of GAG sulfation on Wnt signaling and bone homeostasis. [181] However, GAG-mimicking polymers based on other biopolymers cannot overcome the disadvantages mentioned above, i.e., product heterogeneity and possible immunogenic effects persist. [179] …”

Section: Perspectivementioning

confidence: 99%

Glycosaminoglycan‐Based Biohybrid Hydrogels: A Sweet and Smart Choice for Multifunctional Biomaterials

et al. 2016

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Glycosaminoglycans (GAGs) govern important functional characteristics of the extracellular matrix (ECM) in living tissues. Incorporation of GAGs into biomaterials opens up new routes for the presentation of signaling molecules, providing control over development, homeostasis, inflammation and tumor formation and progression. This review discusses recent approaches to GAG-based materials, highlighting the formation of modular, tunable biohybrid hydrogels by covalent and non-covalent conjugation schemes, including both theory-driven design concepts and advanced processing technologies. Examples of the application of the resulting materials in biomedical studies are provided. For perspective, we highlight solid-phase and chemoenzymatic oligosaccharide synthesis methods for GAG-derived motifs, rational and high-throughput design strategies for GAG-based materials and the utilization of the factor-scavenging characteristics of GAGs.

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“…Sulfated HA showed selective binding, as measured by surface plasmon resonance (SPR), for isoform 165a of vascular endothelial growth factor (VEGF 165a ) 46 and sclerostin, a secreted glycoprotein that has an integral role in bone biology. 47 Integration of in silico (molecular docking and dynamics simulations) and in vitro SPR studies showed that binding to sclerostin was dependent on the degree and pattern of HA sulfation. Others showed that increased sulfation of HA resulted in higher binding affinity to TGF-β1 compared with native HA or chondroitin sulfate.…”

Section: Introductionmentioning

confidence: 99%

Impact of structurally modifying hyaluronic acid on CD44 interaction

et al. 2017

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CD44 is a widely-distributed type I transmembrane glycoprotein that binds hyaluronic acid (HA) in most cell types, including primary tumor cells and cancer-initiating cells and has roles in cell migration, cell-cell, and cell-matrix adhesion. HA-derived conjugates and nanoparticles that target the CD44 receptor on cells have been reported for targeted delivery of therapeutics and imaging agents. Altering crucial interactions of HA with CD44 active sites holds significant importance in modulating targeting ability of hyaluronic acid to other cancer types that do not express the CD44 receptor or minimizing the interaction with CD44+ cells that are not target cells. The approach adopted here was deacetylation of the N-acetyl group and selective sulfation on the C6-OH on the HA polymer, which form critical interactions with the CD44 active site. Major interactions identified by molecular modeling were confirmed to be hydrogen bonding of the C6-OH with Tyr109 and hydrophobic interaction of the N-acetyl group with Tyr46, 83 and Ile 92. Modified HA was synthesized and characterized and its interactions were assessed by in vitro and molecular modeling approaches. In vitro techniques included flow cytometry and fluorescence polarization, while in silico approaches included docking and binding calculations by a MM-PBSA approach. These studies indicated that while both deacetylation and sulfation of HA individually decrease CD44 interaction, both chemical modifications are required to minimize interaction with CD44+ cells. The results of this study represent the first step to effective retargeting of HA-derived NPs for imaging and drug delivery.

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Structural and functional insights into sclerostin-glycosaminoglycan interactions in bone

Cited by 41 publications

References 25 publications

Novel actions of sclerostin on bone

Novel actions of sclerostin on bone

Glycosaminoglycan‐Based Biohybrid Hydrogels: A Sweet and Smart Choice for Multifunctional Biomaterials

Impact of structurally modifying hyaluronic acid on CD44 interaction

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