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Hypoxia and acidosis are recognized features of inflammatory arthroses. This study describes the effects of IGF-1 and TGF-β(1) on pH regulatory mechanisms in articular cartilage under hypoxic conditions. Acid efflux, reactive oxygen species (ROS), and mitochondrial membrane potential were measured in equine articular chondrocytes isolated in the presence of serum (10% fetal calf serum), IGF-1 (1, 10, 50, 100 ng/ml) or TGF-β(1) (0.1, 1, 10 ng/ml) and then exposed to a short-term (3 h) hypoxic insult (1% O(2)). Serum and 100 ng/ml IGF-1 but not TGF-β(1) attenuated hypoxic regulation of pH homeostasis. IGF-1 appeared to act through mitochondrial membrane potential stabilization and maintenance of intracellular ROS levels in very low levels of oxygen. Using protein phosphorylation inhibitors PD98059 (25 µM) and wortmannin (200 nM) and Western blotting, ERK1/2 and PI-3 kinase pathways are important for the effect of IGF-1 downstream to ROS generation in normoxia but only PI-3 kinase is implicated in hypoxia. These results show that oxygen and growth factors interact to regulate pH recovery in articular chondrocytes by modulating intracellular oxygen metabolites.

Original publication

DOI

10.1002/jor.22221

Type

Journal article

Journal

J Orthop Res

Publication Date

02/2013

Volume

31

Pages

197 - 203

Keywords

Acid-Base Equilibrium, Androstadienes, Animals, Cartilage, Articular, Chondrocytes, Flavonoids, Homeostasis, Horses, Hydrogen-Ion Concentration, Hypoxia, Insulin-Like Growth Factor I, MAP Kinase Signaling System, Membrane Potential, Mitochondrial, Oxygen, Phosphatidylinositol 3-Kinases, Phosphorylation, Reactive Oxygen Species, Transforming Growth Factor beta, Wortmannin