Cellular and Molecular Biology



Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: Putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes

A. Mobasheri1, S. Richardson2, R. Mobasheri3, M. Shakibaei4 and J.A. Hoyland2

1Molecular Pathogenesis and Connective Tissue Research Groups, Faculty of Veterinary Science, University of Liverpool, Liverpool, United Kingdom, 2Divison of Laboratory and Regenerative Medicine, School of Medicine, University of Manchester, Manchester, United Kingdom, 3Department of Trauma and Orthopaedics, Worthing Hospital, Worthing, West Sussex, United Kingdom, 4Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Germany

Offprint requests to: Dr. A. Mobasheri, Department of Veterinary Preclinical Sciences, Faculty of Veterinary Science, University of Liverpool, Liverpool L69 7ZJ, United Kingdom. e-mail: a.mobasheri@liverpool.ac.uk

Summary. Articular cartilage is an avascular connective tissue in which the availability of oxygen and glucose is significantly lower than synovial fluid and plasma. Glucose is an important metabolic fuel and structural precursor that plays a key role in the synthesis of extracellular matrix macromolecules in articular cartilage. However, glucose concentrations in cartilage can fluctuate depending on age, physical activity and endocrine status. Chondrocytes are glycolytic cells and must be able to sense the quantities of oxygen and glucose available to them in the extracellular matrix and respond appropriately by adjusting cellular metabolism. Consequently chondrocytes must have the capacity to survive in an extracellular matrix with limited nutrients and low oxygen tensions. The molecular mechanisms responsible for allowing chondrocytes to adapt to these harsh environmental conditions are poorly understood. In this article we present a novel “dual” model of oxygen and glucose sensing in chondrocytes based on recent experimental data. This model incorporates the hypoxia-inducible factor alpha (HIF-1a) as an oxygen sensor and the hypoxia responsive facilitative glucose transporters, GLUT1 and GLUT3 as putative components of the glucose sensing apparatus in chondrocytes. Recent studies have shown that GLUT1 and GLUT3 are both expressed in chondrocytes and their HIF-1a-mediated transcription may be dually stimulated in response to hypoxia and low glucose conditions which in turn promote anaerobic glycolysis in favor of oxidative phosphorylation. This working model provides, for the first time, a unifying hypothesis to explain how chondrocytes might sense and respond to low oxygen tensions and alterations in extracellular glucose. Histol Histopathol 20, 1327-1338 (2005)

Key words: Articular cartilage, Chondrocyte, Oxygen-regulated transcription factor, Hypoxia-inducible factor alpha, Glucose sensing, Glucose transporter, GLUT1, GLUT3

DOI: 10.14670/HH-20.1327