The role of CCN2 in cartilage and bone development

Abstract

CCN2, a classical member of the CCN family of matricellular proteins, is a key molecule that conducts cartilage development in a harmonized manner through novel molecular actions. During vertebrate development, all cartilage is primarily formed by a process of mesenchymal condensation, while CCN2 is induced to promote this process. Afterwards, cartilage develops into several subtypes with different fates and missions, in which CCN2 plays its proper roles according to the corresponding microenvironments. The history of CCN2 in cartilage and bone began with its re-discovery in the growth cartilage in long bones, which determines the skeletal size through the process of endochondral ossification. CCN2 promotes physiological developmental processes not only in the growth cartilage but also in the other types of cartilages, i.e., Meckel’s cartilage representing temporary cartilage without autocalcification, articular cartilage representing hyaline cartilage with physical stiffness, and auricular cartilage representing elastic cartilage. Together with its significant role in intramembranous ossification, CCN2 is regarded as a conductor of skeletogenesis. During cartilage development, the CCN2 gene is dynamically regulated to yield stage-specific production of CCN2 proteins at both transcriptional and post-transcriptional levels. New functional aspects of known biomolecules have been uncovered during the course of investigating these regulatory systems in chondrocytes. Since CCN2 promotes integrated regeneration as well as generation (=development) of these tissues, its utility in regenerative therapy targeting chondrocytes and osteoblasts is indicated, as has already been supported by experimental evidence obtained in vivo.

Expression profles of human CCN genes in patients with osteoarthritis or rheumatoid arthritis

“…Thus, CCN2 likely figures strongly in skeletogenesis. Although high expression of CCN2 in knee OA cartilage has been reported [11], no studies on CCN2 in hip OA cartilage or OA or RA synoviums have been conducted to date. In the present investigation, CCN2 was the most abundantly expressed among all CCN genes in the synoviums and cartilage of patients with advanced OA and RA.…”

Role of low-density lipoprotein receptor related protein 1 (LRP1) in CCN2/connective tissue growth factor (CTGF) protein transport in chondrocytes

“…In our series of studies, we have uncovered crucial roles of CCN family member 2 (CCN2; also known as connective tissue growth factor, CTGF) in endochondral ossification (Ivkovic et al, 2003;Kubota and Takigawa, 2011;Nakanishi et al, 1997;Nakanishi et al, 2000;Nishida et al, 2002;Perbal and Takigawa, 2005;Takigawa et al, 2003) and regeneration of articular cartilage (Nishida et al, 2004). Interestingly, in vivo, CCN2 molecules are distributed in a layer different from that containing the Ccn2-mRNA-positive cells.…”

CCN2 in orofacial tissue development and remodeling

“…Upon delivery, the initial skull of a baby is composed of more than 40 elements, which eventually fuse into 22 bones to constitute the adult skull. Among them, the major parts supporting the brain are formed through a developmental pathway entitled endochondral ossification [3,25]. Endochondral ossification is a sophisticated biological process established during vertebrate evolution.…”