CHD2 and osteoarthritis: For Tb.Th the strongest candidate genes were Pcsk6, Rgma, and Chd2. Pcsk6 encodes paired amino acid converting enzyme 4 (PACE4) which, in human females, evokes proteolytic degradation of aggrecan, a major cartilage molecule, by activating the proteases ADAMTS-4 and pro-ADAMTS-4, thereby inducing the development of osteoarthritis [45].