Hypoxia-inducible factor-2α induces expression of type X collagen and matrix metalloproteinases 13 in osteoarthritic meniscal cells

To evaluate whether Hypoxia-inducible factor-2 alpha (HIF-2 alpha) regulates expression of endochondral ossification-related molecules in human OA meniscus. Expressions of HIF-2 alpha, type X collagen (COL10), matrix metalloproteinase (MMP)-13, and vascular endothelial growth factor (VEGF) in non-OA and OA menisci were analyzed by real-time RT-PCR and immunohistochemistry (IHC). Meniscal cells from OA patients were treated with interleukin-1 beta (IL-1 beta) and gene expression was analyzed. After knockdown of HIF-2 alpha in OA meniscal cells, COL10 and MMP-13 expression were analyzed by RT-PCR, western blotting, immunofluorescence and ELISA. Histological analysis demonstrated weak staining of the superficial layer and large round cells in OA meniscus. RT-PCR analysis showed that HIF-2 alpha, COL10, MMP-13, and VEGF mRNA expressions were higher in OA than non-OA meniscal cells. IHC showed a coordinated staining pattern of HIF-2 alpha, COL10, and MMP-13 in OA meniscus. IL-1 beta treatment increased HIF-2 alpha, COL10, and MMP-13 expressions in OA meniscal cells, and knockdown of HIF-2 alpha suppressed IL-1 beta-mediated increase in COL10 and MMP-13 expression. These results suggested that HIF-2 alpha may cause meniscal matrix degradation by transactivation of MMP-13. HIF-2 alpha may be a therapeutic target for modulating matrix degradation in both articular cartilage and meniscus during knee OA progression.