title: The promotion of osteoclastogenesis by sulfated hyaluronan through interference with osteoprotegerin and receptor activator of NF-κB ligand/osteoprotegerin complex formation.
abstract: In order to improve bone regeneration, in particular in aged and multimorbid patients, the development of new adaptive biomaterials and their characterization in terms of their impact on bone biology is warranted. Glycosaminoglycans (GAGs) such as hyaluronan (HA) are major extracellular matrix (ECM) components in bone and may display osteogenic properties that are potentially useful for biomaterial coatings. Using native and synthetically derived sulfate-modified HA, we evaluated how GAG sulfation modulates the activity of two main regulators of osteoclast function: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). GAGs were tested for their capability to bind to OPG and RANKL using surface plasmon resonance (SPR), ELISA and molecular modeling techniques. Results were validated in an in vitro model of osteoclastogenesis. Sulfated GAGs bound OPG but not RANKL in a sulfate-dependent manner. Furthermore, OPG pre-incubated with different GAGs displayed a sulfate- and dose-dependent loss in bioactivity, possibly due to competition of GAGs for the RANKL/OPG binding site revealing a potential GAG interaction site at the RANKL/OPG interface. In conclusion, high-sulfated GAGs might significantly control osteoclastogenesis via interference with the physiological RANKL/OPG complex formation. Whether these properties can be utilized to improve bone regeneration and fracture healing needs to be validated in vivo.
authors.affiliation: Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III, Dresden Technical University Medical Center, D-01307 Dresden, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Salbach-Hirsch
authors.forename: Julia
authors.initials: J
authors.lastname: Kraemer
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Samsonov
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pisabarro
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moeller
authors.forename: Matthias
authors.initials: M
authors.lastname: Schnabelrauch
authors.forename: Dieter
authors.initials: D
authors.lastname: Scharnweber
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.forename: Vera
authors.initials: V
authors.lastname: Hintze
mesh_terms: D000818:Animals; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D006820:Hyaluronic Acid / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D053244:Osteoprotegerin / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D053244:Osteoprotegerin; D053246:Receptor Activator of Nuclear Factor-kappa B; D006820:Hyaluronic Acid
keywords: Hyaluronic acid/hyaluronan (HA) sulfate; Osteoclast (OC); Osteoprotegerin (OPG); Receptor activator of NF-κB ligand (RANKL); Surface plasmon resonance (SPR)