CCN Family Genes in the Development and Regeneration of Cartilage

The CCN family consists of 6 members with structural and functional similarities and has been recently attracting the interest of a number of researchers. The gene products are commonly characterized by the tetramodular structure, with an exception of CCN5 lacking the C-terminal module. In general, each single module is highly interactive with other molecules, which enables the CCN proteins to act as a modulator of extracellular signaling networks. Interestingly, cartilage is a tissue in which almost all the members are thought to be involved in its development. Over years, our group has been investigated the expression and function of a classical member, CCN2/connsctive tissue growth factor (CTGF) along with endochondral ossification and articular cartilage regeneration. As a signaling modulator, CCN2 promotes the proper phenotypes of every type of chondrocytes examined without triggering ectopic or atypical phenotypes, which was best represented in the regeneration of damaged articular cartilage by CCN2 in animal models. During both development and regeneration, ccn2 gene expression is duly regulated to supply CCN2 at the location and time in necessity. Recently, we have clarified the post-transcriptional regulatory systems to realize the controlled expression along with such biological events. In these regulatory systems, secondary-structured RNA elements in the 3'-untranslated region of ccn2 gene are mediating the control of mRNA degradation and translation under the collaboration with specific binding protein counterparts. Of note, our most recent data indicated that not only ccn2, but also all other members were expressed differentially in growth plate cartilage of developing mice. Particularly, the CCN4 gene comprised a splicing variant in normal chondrocytes, which has never been found except for a few malignancies, suggesting its critical role in cartilage growth and/or development. Further investigation of the other members is also ongoing, and the current outcome may be presented on site.