Regeneration of Defects in Articular Cartilage in Rat Knee Joints by CCN2 (Connective Tissue Growth Factor)

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  • Takashi Nishida
    Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
  • Satoshi Kubota
    Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
  • Shunji Kojima
    Department of Oral and Maxillofacial Rehabilitation, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
  • Takuo Kuboki
    Department of Oral and Maxillofacial Rehabilitation, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
  • Kyouji Nakao
    Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
  • Toshihiro Kushibiki
    Institute for Frontier Medical Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Yasuhiko Tabata
    Institute for Frontier Medical Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Masaharu Takigawa
    Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>Conclusion: These findings suggest the utility of CTGF/CCN2 in the regeneration of articular cartilage.</jats:p>

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