title: Sulfated hyaluronan improves bone regeneration of diabetic rats by binding sclerostin and enhancing osteoblast function.
abstract: Bone fractures in patients with diabetes mellitus heal poorly and require innovative therapies to support bone regeneration. Here, we assessed whether sulfated hyaluronan included in collagen-based scaffold coatings can improve fracture healing in diabetic rats. Macroporous thermopolymerized lactide-based scaffolds were coated with collagen including non-sulfated or sulfated hyaluronan (HA/sHA3) and inserted into 3 mm femoral defects of non-diabetic and diabetic ZDF rats. After 12 weeks, scaffolds coated with collagen/HA or collagen/sHA3 accelerated bone defect regeneration in diabetic, but not in non-diabetic rats as compared to their non-coated controls. At the tissue level, collagen/sHA3 promoted bone mineralization and decreased the amount of non-mineralized bone matrix. Moreover, collagen/sHA3-coated scaffolds from diabetic rats bound more sclerostin in vivo than the respective controls. Binding assays confirmed a high binding affinity of sHA3 to sclerostin. In vitro, sHA3 induced BMP-2 and lowered the RANKL/OPG expression ratio, regardless of the glucose concentration in osteoblastic cells. Both sHA3 and high glucose concentrations decreased the differentiation of osteoclastic cells. In summary, scaffolds coated with collagen/sHA3 represent a potentially suitable biomaterial to improve bone defect regeneration in diabetic conditions. The underlying mechanism involves improved osteoblast function and binding sclerostin, a potent inhibitor of Wnt signaling and osteoblast function.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolic Bone Diseases, Department of Medicine III, TU Dresden Medical Center, Dresden, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Picke
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolic Bone Diseases, Department of Medicine III, TU Dresden Medical Center, Dresden, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Salbach-Hirsch
authors.affiliation: Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden, Dresden, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Hintze
authors.affiliation: Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rother
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolic Bone Diseases, Department of Medicine III, TU Dresden Medical Center, Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Institute for Pharmacy, Pharmaceutical Technology, University Leipzig, Leipzig, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kascholke
authors.affiliation: Biomaterials Department, INNOVENT e. V., Jena, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Möller
authors.affiliation: Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Bernhardt
authors.affiliation: Department of Trauma and Reconstruction Surgery, TU Dresden Medical Center, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rammelt
authors.affiliation: Structural Bioinformatics, BIOTEC, Technische Universität Dresden, Dresden, Germany.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pisabarro
authors.affiliation: Structural Bioinformatics, BIOTEC, Technische Universität Dresden, Dresden, Germany.
authors.forename: Gloria
authors.initials: G
authors.lastname: Ruiz-Gómez
authors.affiliation: Biomaterials Department, INNOVENT e. V., Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schnabelrauch
authors.affiliation: Institute for Pharmacy, Pharmaceutical Technology, University Leipzig, Leipzig, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schulz-Siegmund
authors.affiliation: Institute for Pharmacy, Pharmaceutical Technology, University Leipzig, Leipzig, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hacker
authors.affiliation: Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Scharnweber
authors.affiliation: University Center of Orthopedics and Traumatology, TU Dresden Medical Center, Dresden, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hofbauer
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolic Bone Diseases, Department of Medicine III, TU Dresden Medical Center, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden, Germany; Center for Healthy Aging, TU Dresden Medical Center, Dresden, Germany. Electronic address: lorenz.hofbauer@uniklinikum-dresden.de.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001861:Bone Regeneration / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D002113:Calcification, Physiologic / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D004146:Dioxanes / Q000737:chemistry; D005819:Genetic Markers; D005947:Glucose / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000494:pharmacology; D006820:Hyaluronic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D058105:Polymerization; D011485:Protein Binding / Q000187:drug effects; D000067996:RAW 264.7 Cells; D051381:Rats; D013431:Sulfates / Q000494:pharmacology*; D013696:Temperature; D054457:Tissue Scaffolds / Q000737:chemistry
chemical_list: D019485:Bone Morphogenetic Proteins; D020099:Coated Materials, Biocompatible; D004146:Dioxanes; D005819:Genetic Markers; D006025:Glycosaminoglycans; C486031:Sost protein, rat; D013431:Sulfates; D006820:Hyaluronic Acid; D003094:Collagen; C091880:dilactide; D005947:Glucose
keywords: Defect healing; Glycosaminoglycans (GAG); Hyaluronic acid/hyaluronan (HA) sulfate; Sclerostin; Type 2 diabetes mellitus