A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice

Growth and differentiation factor 5 (GDF5) has been implicated in chondrogenesis and joint formation, and anassociation of GDF5 and osteoarthritis (OA) has been reported recently. However, thein vivo function ofGDF5 remains mostly unclarified. Although various humanGDF5 mutations and their phenotypic conse-quences have been described, only loss-of-function mutations that cause brachypodism (shortening andjoint ankylosis of the digits) have been reported in mice. Here, we report a new Gdf5 allele derived from alarge-scale N-ethyl-N-nitrosourea mutagenesis screen. This allele carries an amino acid substitution(W408R) in a highly conserved region of the active signaling domain of the GDF5 protein. The mutation issemi-dominant, showing brachypodism and ankylosis in heterozygotes and much more severe brachypod-ism, ankylosis of the knee joint and malformation with early-onset OA of the elbow joint in homozygotes.The mutant GDF5 protein is secreted and dimerizes normally, but inhibits the function of the wild-typeGDF5 protein in a dominant-negative fashion. This study further highlights a critical role of GDF5 in joint for-mation and the development of OA, and this mouse should serve as a good model for OA.INTRODUCTIONOsteoarthritis (OA, MIM 165720) is the most common form ofjoint disorder and is characterized by the degeneration ofarticular cartilage. There are apparent genetic influenceson OA (1–4): a number of genetic loci associated with OA(5–7) as well as specific associations between certain genesand OA (8–13) have been reported. The precise etiology ofthe disease is still unknown; however, a few animal modelsof OA produced by gene-targeting techniques have beencreated (14,15).Growth and differentiation factor 5 (GDF5), also known ascartilage-derived morphogenetic protein 1, is a member of thebone morphogenic protein (BMP) family that are secretorysignaling molecules binding to specific serine–threoninekinase receptors. Gdf5 is expressed in osteochondral progeni-tors of the appendicular (16–18) and axial skeleton. Duringearly limb development, Gdf5 is expressed in the condensing# The Author 2007. Published by Oxford University Press. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournals.org