Sulfated hyaluronan improves bone regeneration of diabetic rats by binding sclerostin and enhancing osteoblast function

Biomaterials. 2016 Jul;96:11-23. doi: 10.1016/j.biomaterials.2016.04.013. Epub 2016 Apr 21.

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.

Keywords: Defect healing; Glycosaminoglycans (GAG); Hyaluronic acid/hyaluronan (HA) sulfate; Sclerostin; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Regeneration / drug effects*
  • Bone Remodeling / drug effects
  • Calcification, Physiologic / drug effects
  • Coated Materials, Biocompatible / pharmacology
  • Collagen / pharmacology
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetes Mellitus, Type 2 / pathology
  • Dioxanes / chemistry
  • Genetic Markers
  • Glucose / pharmacology
  • Glycosaminoglycans / pharmacology
  • Hyaluronic Acid / pharmacology*
  • Male
  • Mice
  • Organ Size / drug effects
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteogenesis / drug effects
  • Polymerization
  • Protein Binding / drug effects
  • RAW 264.7 Cells
  • Rats
  • Sulfates / pharmacology*
  • Temperature
  • Tissue Scaffolds / chemistry

Substances

  • Bone Morphogenetic Proteins
  • Coated Materials, Biocompatible
  • Dioxanes
  • Genetic Markers
  • Glycosaminoglycans
  • Sost protein, rat
  • Sulfates
  • Hyaluronic Acid
  • Collagen
  • dilactide
  • Glucose