Roles for Itih1 and Itih2 have not been reported in the valve, but in arthritis, pathological degradation of cartilage has been attributed to ITI-HA complexes serving as substrates for ECM proteases—including ADAMTS-5 [29], which has been described as a key player in myxomatous valve disease [30]. This evidence concerns the gene ITIH1 and arthritic joint disease.