Metabolic regulation of the CCN family genes by glycolysis in chondrocytes
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The CCN family consists of 6 genes in the mammalian genome and produces multifunctional proteins involved in a variety of biological processes. Recent reports indicate the profound roles of CCN2 in energy metabolism in chondrocytes, and Ccn2 deficiency is known to alter the expression of 2 other family members including Ccn3. However, almost nothing is known concerning the regulation of the CCN family genes by energy metabolism. In order to gain insight into this critical issue, we initially and comprehensively evaluated the effect of inhibition of glycolysis on the expression of all of the CCN family genes in chondrocytic cells. Upon the inhibition of a glycolytic enzyme, repression of CCN2 expression was observed, whereas CCN3 expression was conversely induced. Similar repression of CCN2 was conferred by the inhibition of aerobic ATP production, which, however, did not induce CCN3 expression. In contrast, glucose starvation significantly enhanced the expression of CCN3 in those cells. The results of a reporter gene assay using a molecular construct containing a CCN3 proximal promoter revealed a dose-dependent induction of the CCN3 promoter activity by the glycolytic inhibitor in chondrocytic cells. These results unveiled a critical role of glycolytic activity in the regulation of CCN2 and CCN3, which activity mediated the mutual regulation of these 2 major CCN family members in chondrocytes.
KeywordsCCN2 CCN3 Glycolysis Metabolism Cartilage
The authors thank Drs. Takako Hattori, Kazumi Kawata, Eriko Aoyama for their helpful support in experiments, as well as Ms. Yoshiko Miyake for her secretarial assistance. This study was supported by grants from the program Grants-in-aid for Scientific Research (B) [JP15H0514 to M.T.], and for Challenging Research (Exploratory) [JP17K19757 to M.T. and JP17K19756 to S.K.] from the Japan Society for the Promotion of Science.
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