In the pathogenesis of osteoarthritis, HIF-2α regulates subchondral bone sclerosis, the formation of osteophytes in joints, and RA; this process occurs via the direct or indirect (via IL-6 signaling) upregulation of matrix-degrading catabolic enzymes, such as MMP-3 and MMP-13, and the Fas-mediated apoptosis of chondrocytes60–62. This evidence concerns the gene MMP3 and rheumatoid arthritis.