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Hypoxia‐inducible factor 1α inhibits the fibroblast‐like markers type I and type III collagen during hypoxia‐induced chondrocyte redifferentiation: Hypoxia not only induces type II collagen and aggrecan, but it also inhibits type I and type III collagen in the hypoxia‐inducible factor 1α–dependent redifferentiation of chondrocytes
Ist Teil von
Arthritis and rheumatism, 2009-10, Vol.60 (10), p.3038-3048
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2009
Quelle
Wiley Online Library
Beschreibungen/Notizen
Objective
Autologous chondrocyte implantation requires expansion of cells ex vivo, leading to dedifferentiation of chondrocytes (loss of aggrecan and type II collagen to the profit of type I and type III collagens). Several approaches have been described for redifferentiation of these cells. Among them, low oxygen tension has been exploited to restore the differentiated chondrocyte phenotype, but molecular mechanisms of this process remain unclear. However, under conditions of hypoxia, one of the major factors involved is hypoxia‐inducible factor 1α (HIF‐1α). The purpose of this study was to investigate the role of HIF‐1α during human chondrocyte redifferentiation.
Methods
We used complementary approaches to achieving HIF‐1α loss (inhibition by cadmium ions and dominant‐negative expression) or gain (ectopic expression and cobalt ion treatment) of function. Expression of chondrocyte, as well as fibroblast‐like, phenotype markers was determined using real‐time reverse transcription–polymerase chain reaction and Western blot analyses. Binding activities of HIF‐1α and SOX9, a pivotal transcription factor of chondrogenesis, were evaluated by electrophoretic mobility shift assays and by chromatin immunoprecipitation assay.
Results
We found that hypoxia and HIF‐1α not only induced the expression of SOX9, COL2A1, and aggrecan, but they simultaneously inhibited the expression of COL1A1, COL1A2, and COL3A1. In addition, we identified the binding of HIF‐1α to the aggrecan promoter, the first such reported demonstration of this binding.
Conclusion
This study is the first to show a bimodal role of HIF‐1α in cartilage homeostasis, since HIF‐1α was shown to favor specific markers and to impair dedifferentiation. This suggests that manipulation of HIF‐1α could represent a promising approach to the treatment of osteoarthritis.