Activin A/BMP2 chimera AB235 drives efficient redifferentiation of long term cultured autologous chondrocytes

Sci Rep. 2015 Nov 13;5:16400. doi: 10.1038/srep16400.

Abstract

Autologous chondrocyte implantation (ACI) depends on the quality and quantity of implanted cells and is hindered by the fact that chondrocytes cultured for long periods of time undergo dedifferentiation. Here we have developed a reproducible and efficient chondrogenic protocol to redifferentiate chondrocytes isolated from osteoarthritis (OA) patients. We used morphological, histological and immunological analysis together with a RT-PCR detection of collagen I and collagen II gene expression to show that chondrocytes isolated from articular cartilage biopsies of patients and subjected to long-term culture undergo dedifferentiation and that these cells can be redifferentiated following treatment with the chimeric Activin A/BMP2 ligand AB235. Examination of AB235-treated cell pellets in both in vitro and in vivo experiments revealed that redifferentiated chondrocytes synthesized a cartilage-specific extracellular matrix (ECM), primarily consisting of vertically-orientated collagen fibres and cartilage-specific proteoglycans. AB235-treated cell pellets also integrated into the surrounding subcutaneous tissue following transplantation in mice as demonstrated by their dramatic increase in size while non-treated control pellets disintegrated upon transplantation. Thus, our findings describe an effective protocol for the promotion of redifferentiation of autologous chondrocytes obtained from OA patients and the formation of a cartilage-like ECM that can integrate into the surrounding tissue in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / genetics
  • Activins / metabolism*
  • Aged
  • Animals
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 2 / metabolism*
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology
  • Cell Differentiation*
  • Chondrocytes / pathology*
  • Chondrocytes / transplantation
  • Collagen / genetics
  • Collagen / metabolism
  • Extracellular Matrix / metabolism
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Ligands
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Osteoarthritis / pathology
  • Osteoarthritis / therapy
  • Proteoglycans / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transplantation, Autologous
  • Transplantation, Heterologous

Substances

  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Ligands
  • Proteoglycans
  • activin A
  • Activins
  • Collagen