Local delivery of a carbohydrate analog for reducing arthritic inflammation and rebuilding cartilage

Biomaterials. 2016 Mar;83:93-101. doi: 10.1016/j.biomaterials.2015.12.029. Epub 2015 Dec 31.

Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation. Because OA has a multifactorial nature and complex interrelationship of the individual elements of a whole joint, there is a need for comprehensive therapeutic approaches for cartilage tissue engineering, which simultaneously address multiple aspects of disease etiology. In this work, we investigated a multifunctional carbohydrate-based drug candidate, tri-butanoylated N-acetyl-D-galactosamine analog (3,4,6-O-Bu3GalNAc) that induced cartilage tissue production by human mesenchymal stem cells (hMSCs) and human OA chondrocytes by modulating Wnt/β-catenin signaling activity. The dual effects promoted chondrogenesis of human MSC and reduced inflammation of human OA chondrocytes in in vitro cultures. Translating these findings in vivo, we evaluated therapeutic effect of 3,4,6-O-Bu3GalNAc on the rat model of posttraumatic OA when delivered via local intra-articular sustained-release delivery using microparticles and found this method to be efficacious in preventing OA progression. These results show that 3,4,6-O-Bu3GalNAc, a disease modifying OA drug candidate, has promising therapeutic potential for articular cartilage repair.

Keywords: Carbohydrates; Disease-modifying OA drug; Drug delivery; Mesenchymal stem cells; Osteoarthritis; Tissue engineering.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Biomarkers / metabolism
  • Cartilage, Articular / drug effects
  • Cartilage, Articular / pathology*
  • Cell Differentiation / drug effects
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Chondrogenesis / drug effects
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Galactosamine / chemistry
  • Galactosamine / pharmacology
  • Galactosamine / therapeutic use*
  • Humans
  • Inflammation / complications
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Male
  • Osteoarthritis / complications
  • Osteoarthritis / drug therapy*
  • Osteoarthritis / pathology
  • Rats, Sprague-Dawley
  • Regeneration* / drug effects

Substances

  • Anti-Inflammatory Agents
  • Biomarkers
  • Galactosamine