Molecular Diversity of Facilitative Glucose Transporters in Articular Chondrocytes

In order to appreciate the physiological basis for the molecular diversity of facilitative glucose transporters in chondrocytes we need to re-examine the importance of glucose as a nutrient and structural precursor. Glucose is an important nutrient in fully developed articular cartilage due to the poor vascularization and highly glycolytic nature of the tissue, a situation that is further exacerbated by low oxygen tensions and ongoing anaerobic glycolysis by chondrocytes (Mobasheri et al. 2002c; Otte 1991; Rajpurohit et al. 2002). Therefore, even modest changes in glucose concentrations in the extracellular microenvironment of chondrocytes could impair anabolic and catabolic activities (Mobasheri et al. 2002c; Shikhman et al. 2001a). Fully developed adult chondrocytes express mRNA for multiple isoforms of the GLUT/SLC2A family of glucose transporters including GLUT1, GLUT3, GLUT5, GLUT6, GLUT8, GLUT9, GLUT10, GLUT11, and GLUT12 (Mobasheri et al. 2002b, 2002c; Richardson et al. 2003; Shikhman et al. 2001a) (Fig. 8). The reason for such GLUT isoform diversity in chondrocytes has not yet been satisfactorily explained but several hypotheses have been put forward: GLUT isoform diversity in chondrocytes suggests that the transmembrane uptake of glucose, fructose, and other related hexose sugars is highly specialized and requires several proteins with the capacity to transport structurally different sugars. The observed diversity of GLUT proteins in chondrocytes may possibly reflect a cartilage-specific requirement for ‘fast’ (i.e., GLUT3) and baseline (GLUT1) glucose transporters that operate more efficiently at low substrate concentrations under physiological conditions (Mobasheri et al. 2002c; Richardson et al. 2003). The presence of GLUT1 in chondrocytes has also been linked to the acute requirement of these cells for glycolytic energy metabolism under the low oxygen tension conditions that are prevalent in avascular load-bearing articular cartilage and intervertebral disc (Pfander et al. 2003; Rajpurohit et al. 2002; Schipani et al. 2001). GLUT1 has also been shown to be a cytokine inducible glucose transporter in cartilage since it is induced by catabolic, proinflammatory cytokines (Phillips et al. 2005a; Richardson et al. 2003; Shikhman et al. 2004, 2001a) (Fig. 9).