Catabolic stress induces expression of hypoxia-inducible factor (HIF)-1 alpha in articular chondrocytes: involvement of HIF-1 alpha in the pathogenesis of osteoarthritis

Transcription factor hypoxia-inducible factor (HIF)-1 protein accumulates and activates the transcription of genes that are of fundamental importance for oxygen homeostasis-including genes involved in energy metabolism, angiogenesis, vasomotor control, apoptosis, proliferation, and matrix production-under hypoxic conditions. We speculated that HIF-1 alpha may have an important role in chondrocyte viability as a cell survival factor during the progression of osteoarthritis (OA). The expression of HIF-1 alpha mRNA in human OA cartilage samples was analyzed by real-time PCR. We analyzed whether or not the catabolic factors IL-1 beta and H(2)O(2) induce the expression of HIF-1 alpha in OA chondrocytes under normoxic and hypoxic conditions (O(2) < 6%). We investigated the levels of energy generation, cartilage matrix production, and apoptosis induction in HIF-1 alpha-deficient chondrocytes under normoxic and hypoxic conditions. In articular cartilages from human OA patients, the expression of HIF-1 alpha mRNA was higher in the degenerated regions than in the intact regions. Both IL-1 and H(2)O(2) accelerated mRNA and protein levels of HIF-1 alpha in cultured chondrocytes. Inhibitors for phosphatidylinositol 3-kinase and p38 kinase caused a significant decrease in catabolic-factor-induced HIF-1 alpha expression. HIF-1 alpha-deficient chondrocytes did not maintain energy generation and cartilage matrix production under both normoxic and hypoxic conditions. Also, HIF-1 alpha-deficient chondrocytes showed an acceleration of catabolic stress-induced apoptosis in vitro. Our findings in human OA cartilage show that HIF-1 alpha expression in OA cartilage is associated with the progression of articular cartilage degeneration. Catabolic-stresses, IL-1, and oxidative stress induce the expression of HIF-1 alpha in chondrocytes. Our results suggest an important role of stress-induced HIF-1 alpha in the maintenance of chondrocyte viability in OA articular cartilage.