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.


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


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