Hypoxia promotes production and inhibits destruction of human articular cartilage
Thoms BL., Dudek K., Lafont JE., Murphy CL.
OBJECTIVE.: To determine the effect of hypoxia on both anabolic and catabolic pathways in human articular cartilage and to elucidate the roles played by HIFs in these responses. METHODS.: Normal human articular cartilage from a range of donors was obtained from above-knee amputations due to sarcomas not involving the joint space. Hypoxia and IL-α treatments were performed on both fresh cartilage tissue explants and isolated cells. Cell transfections were performed on isolated human chondrocytes. RESULTS.: Here we show that the resident chondrocytes in human cartilage are exquisitely adapted to hypoxia and use it to regulate tissue-specific metabolism. Using chromatin immunoprecipitation we show that hypoxia induces cartilage production in human tissue explants through direct binding of HIF-2α to a specific site in master-regulator gene SOX9. Importantly, hypoxia also suppressed spontaneous and induced destruction of human cartilage in explant culture. We show that anti-catabolic responses are predominantly mediated by HIF-1α. Manipulation of the hypoxia sensing pathway through depletion of HIF-targeting prolyl hydroxylase PHD2 further enhanced cartilage responses compared to hypoxia alone. Comparing to human cartilage, similar hypoxic regulation of tissue-specific metabolism was observed in pig, but not mouse cartilage. CONCLUSION.: Our data reveal that while fundamental regulators like SOX9 are key for both mouse and man, the way in which they are controlled can differ. This is all the more important since it is such upstream regulators that need to be directly targeted for therapeutic benefit. HIF-targeting hydroxylase PHD2 may represent a relevant target for cartilage repair.