Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor)

  • Nishida T
  • Kubota S
  • Kojima S
 et al. 
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Abstract

CTGF/CCN2, a hypertrophic chondrocyte-specific gene product, possessed the ability to repair damaged articular cartilage in two animal models, which were experimental osteoarthritis and full-thickness defects of articular cartilage. These findings suggest that CTGF/CCN2 may be useful in regeneration of articular cartilage. INTRODUCTION: Connective tissue growth factor (CTGF)/CCN2 is a unique growth factor that stimulates the proliferation and differentiation, but not hypertrophy, of articular chondrocytes in vitro. The objective of this study was to investigate the therapeutic use of CTGF/CCN2. MATERIALS AND METHODS: The effects of recombinant CTGF/CCN2 (rCTGF/CCN2) on repair of damaged cartilage were evaluated by using both the monoiodoacetic acid (MIA)-induced experimental rat osteoarthritis (OA) model and full-thickness defects of rat articular cartilage in vivo. RESULTS: In the MIA-induced OA model, quantitative real-time RT-PCR assays showed a significant increase in the level of CTGF/CCN2 mRNA, and immunohistochemical analysis and in situ hybridization revealed that the clustered chondrocytes, in which clustering indicates an attempt to repair the damaged cartilage, produced CTGF/CCN2. Therefore, CTGF/CCN2 was suspected to play critical roles in cartilage repair. In fact, a single injection of rCTGF/CCN2 incorporated in gelatin hydrogel (rCTGF/CCN2-hydrogel) into the joint cavity of MIA-induced OA model rats repaired their articular cartilage to the extent that it became histologically similar to normal articular cartilage. Next, to examine the effect of rCTGF/CCN2 on the repair of articular cartilage, we created defects (2 mm in diameter) on the surface of articular cartilage in situ and implanted rCTGF/CCN2-hydrogel or PBS-hydrogel therein with collagen sponge. In the group implanted with rCTGF/CCN2-hydrogel collagen, new cartilage filled the defect 4 weeks postoperatively. In contrast, only soft tissue repair occurred when the PBS-hydrogel collagen was implanted. Consistent with these in vivo effects, rCTGF/CCN2 enhanced type II collagen and aggrecan mRNA expression in mouse bone marrow-derived stromal cells and induced chondrogenesis in vitro. CONCLUSION: These findings suggest the utility of CTGF/CCN2 in the regeneration of articular cartilage.

Author-supplied keywords

  • Aggrecans
  • Animals
  • Blotting, Northern
  • Blotting, Southern
  • Bone Regeneration/*drug effects
  • Cartilage, Articular/*drug effects/injuries/physio
  • Cell Differentiation/drug effects
  • Cells, Cultured
  • Chondrocytes/chemistry/drug effects/metabolism
  • Chondrogenesis/drug effects
  • Collagen Type X/genetics
  • Connective Tissue Growth Factor
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Extracellular Matrix Proteins/genetics
  • Gene Expression/genetics
  • Hydrogel/chemistry
  • Immediate-Early Proteins/genetics/metabolism/*phar
  • Immunohistochemistry
  • In Situ Hybridization
  • Intercellular Signaling Peptides and Proteins/gene
  • Iodoacetic Acid/pharmacology
  • Knee Injuries/drug therapy/physiopathology
  • Lectins, C-Type
  • Male
  • Mice
  • Mice, Inbred ICR
  • Osteoarthritis, Knee/chemically induced/*drug ther
  • Proteoglycans/genetics
  • Rats
  • Rats, Wistar
  • Recombinant Proteins/pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stromal Cells/drug effects/metabolism
  • Tenascin/genetics

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Authors

  • T Nishida

  • S Kubota

  • S Kojima

  • T Kuboki

  • K Nakao

  • T Kushibiki

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