title: The effect of the degree of sulfation of glycosaminoglycans on osteoclast function and signaling pathways.
abstract: To meet the growing need for bone replacement of our aging population, development of new adaptive biomaterials is essential. Collagen and glycosaminoglycans (GAGs) such as hyaluronan (HA) and chondroitin sulfate (CS) are major components of the extracellular matrix (ECM) in bone. We manufactured native and sulfate-modified GAG matrices, evaluated how these components modulate different functions of osteoclasts, the cells that resorb bone, and analyzed the underlying mechanisms. GAGs were tested for their effects on osteoclast adhesion, viability, differentiation, morphology, and resorption as well as proteome alterations using murine RAW264.7 cells and primary human osteoclasts. Native and sulfated GAGs were stable and largely non-cytotoxic. Sulfation of GAGs led to a significant inhibition of osteoclast differentiation and resorption, which was largely dependent on the degree of sulfation of GAGs rather than the monosaccharide composition. Sulfation significantly reduced resorptive function by 14% (CS) and 43% (HA). Highly sulfated GAGs dose-dependently suppressed osteoclast differentiation, osteoclast-specific expression of TRAP, cathepsin K, SWAP-70, and OSCAR by 63-95%, and inhibited proteins involved in cytoskeletal rearrangement. In conclusion, highly sulfated GAGs significantly inhibit various functions of bone-resorbing osteoclasts. Whether these properties locally contribute to improved fracture or bone defect 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
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliemt
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.forename: Tilman D
authors.initials: TD
authors.lastname: Rachner
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Stefan
authors.initials: S
authors.lastname: Kalkhof
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Möller
authors.forename: Matthias
authors.initials: M
authors.lastname: Schnabelrauch
authors.forename: Vera
authors.initials: V
authors.lastname: Hintze
authors.forename: Dieter
authors.initials: D
authors.lastname: Scharnweber
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry; D005109:Extracellular Matrix / Q000737:chemistry; D005455:Fluorescent Antibody Technique; D006025:Glycosaminoglycans / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D015151:Immunoblotting; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D040901:Proteomics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006025:Glycosaminoglycans; D006820:Hyaluronic Acid; D003094:Collagen