The role of CTGF as a novel tissue-regenerating factor, regenerin, and its application for medical and dental tissue engineering

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1. Using wild type and/or mutant animals, we found that in addition to endochondral ossification in growth plate, CTGF/CCN2 was involved in secondary ossification center formation, intramembranous ossification, formation of periodontal ligament and articular and auricular cartilages, distraction osteogenesis and repair of tooth extraction socket. In vivo administration of CTGF/CCN2 with gelatin hydrogel into the artificial defect of articular cartilage and bone resulted in repair of these tissues, respectively. Taken together with the finding that platelets contained much CTGF/CCN2, these findings indicate that CTGF/CCN2 functions as a regeneration factor "regenerin".2. We developed CTGF/CCN2 domain-specific antibodies and domain-specific ELISA systems. The function and signal transduction pathway of each domain was different depending on types of cells, such as chondrocytes and endothelial cells. CT domain of CTGF/CCN2 promoted adhesion of mesenchymal stem cells on hydroxyapatite plates, suggesting a possible application for bone regeneration with a combination of CTGF/CCN2 and hydroxyapatite.3. A cis-element in 3'-untranslation region (3'-UTR) of CTGF/CCN2 mRNA, which was involved in destabilization of its mRNA, and a protein, which bound to the element, were found in chondrocytes. The biding between them changed in reverse relation to the process of chondrocyte differentiation. A hypoxia-inducible protein, which stabilized CTGF/CCN2 mRNA by binding to its 3'-UTR was also detected.4. CTGF/CCN2 bound to perlecan, aggrecan and fibronectin, indicating its retention in extracellular matrix. CTGF/CCN2 had collaborative action with M-CSF on cartilage. Low density lipoprotein-related protein I was one of the receptors for CTGF/CCN2 in chondrocytes. Concerning signal transduction pathway of CTGF/CCN2 in chondrocytes, PKC was found as an upstream mediator of ERK and p38MAPK. JNK was involved in cell proliferation. PI3K and PKB were found to be involved in calcification.