CCN2 as a Novel Molecule Supporting Energy Metabolism of Chondrocytes

Abstract

CCN2/connective tissue growth factor (CTGF) is a unique molecule that promotes both chondrocytic differentiation and proliferation through its matricellular interaction with a number of extracellular biomolecules. This apparently contradictory functional property of CCN2 suggests its certain role in basic cellular activities such as energy metabolism, which is required for both proliferation and differentiation. Comparative metabolomic analysis of costal chondrocytes isolated from wild-type and Ccn2-null mice revealed overall impaired metabolism in the latter. Among the numerous metabolites analyzed, stable reduction in the intracellular level of ATP, GTP, CTP, or UTP was observed, indicating a profound role of CCN2 in energy metabolism. Particularly, the cellular level of ATP was decreased by more than 50% in the Ccn2-null chondrocytes. The addition of recombinant CCN2 (rCCN2) to cultured Ccn2-null chondrocytes partly redeemed the cellular ATP level attenuated by Ccn2 deletion. Next, in order to investigate the mechanistic background that mediates the reduction in ATP level in these Ccn2-null chondrocytes, we performed transcriptome analysis. As a result, several metabolism-associated genes were found to have been up-regulated or down-regulated in the mutant mice. Up-regulation of a number of ribosomal protein genes was observed upon Ccn2 deletion, whereas a fewgenes required for aerobic and anaerobic ATP production were down-regulated in the Ccn2-null chondrocytes. Among such genes, reduction in the expression of the enolase 1 gene was of particular note. These findings uncover a novel functional role of CCN2 as a metabolic supporter in the growth-plate chondrocytes, which is required for skeletogenesis in mammals.

Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions

“…Supporting these notions, previous findings conducted in vitro indicate that CCN2 promotes the proliferation, maturation and hypertrophy of growth-plate chondrocytes [1,49]. Recently, it was revealed that CCN2 promotes these apparently opposite cell biological events, i.e., proliferation and differentiation, at least in part by supporting the energy metabolism in chondrocytes [54]. Proliferation, migration, adhesion and tube formation of vascular endothelial cells are also enhanced by CCN2 [4].…”

Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers

“…For example, downregulation of glycolysis-related genes such as Pgm1 , Pgam1 , and Eno1 , and decrease in glycolytic activity and ATP levels have been reported in chondrocytes from Ctgf ( Ccn2 )-null mice (Maeda-Uematsu et al, 2014; Murase et al, 2015). It is likely that CTGF regulates expression of glycolysis-related genes after hyperthermia to prevent cancer cells from energy-stressed cell death.…”

New functional aspects of CCN2 revealed by trans-omic approaches

“…Consistent with these data, the other high-energy bearing trinucleotides, GTP, UTP, and CTP, were also less abundant in Ccn2-null chondrocytes. As such, a novel function of CCN2 that supports the energy metabolism of chondrocytes was uncovered by a metabolomics approach [65].…”

“…However, it should be noted that, even in the absence of CCN2, chondrocytes remain viable, proliferative, and capable of producing cartilaginous ECM molecules, albeit at reduced levels. Thus, CCN2 is not solely required for maintaining the basal activity of chondrocytes, but helps them to be more biologically active [65].…”