GDF5 coordinates bone and joint formation during digit development

A functional skeletal system requires the coordinated development of many d ifferent tissue types, including cartilage, bones, joints, and tendons. Mem bers of the Bone morphogenetic protein (BMP) family of secreted signaling m olecules have been implicated as endogenous regulators of skeletal developm ent. This is based on their expression during bone and joint formation, the ir ability to induce ectopic bone and cartilage, and the skeletal abnormali ties present in animals with mutations in BMP family members. One member of this family, Growth/differentiation factor 5 (GDF5), is encoded by the mou se brachypodism locus. Mice with mutations in this gene show reductions in the length of bones in the limbs, altered formation of bones and joints in the sternum, and a reduction in the number of bones in the digits. The expr ession pattern of Gdf5 during normal development and the phenotypes seen in mice with single or double mutations in Gdf5 and Bmp5 suggested that Gdf5 has multiple functions in skeletogenesis, including roles in joint and cart ilage development. To further understand the function of GDF5 in skeletal d evelopment, we assayed the response of developing chick and mouse limbs to recombinant GDF5 protein. The results from these assays, coupled with an an alysis of the development of brachypodism digits, indicate that GDF5 is nec essary and sufficient for both cartilage development and the restriction of joint formation to the appropriate location. Thus, GDF5 function in the di gits demonstrates a link between cartilage development and joint developmen t and is an important determinant of the pattern of bones and articulations in the digits, (C) 1999 Academic Press.