Expression and Function ofGdf-5during Digit Skeletogenesis in the Embryonic Chick Leg Bud

Abstract

Bone morphogenetic proteins (BMPs) constitute a large family of secreted signals involved in the formation of the skeleton but the specific function of each member of this family remains elusive. GDF-5 is a member of the BMP family which has been implicated in several skeletogenic events including the induction and growth of the appendicular cartilages, the determination of joint forming regions, and the establishment of tendons. Here, we have studied the function of GDF-5 in digit skeletogenesis by analyzing the effects of its local administration in the developing autopod of embryonic chick and the regulation of its pattern of gene expression by other signals involved in digit morphogenesis. As reported in the mouse, the gdf-5 gene exhibits a precise distribution in the joint-forming regions of the developing chicken digital rays. GDF-5 beads implanted at the tip of the digits promote intense cartilage growth and fail to induce morphological or molecular signs of joint formation. Furthermore, GDF-5 beads implanted in the interdigits inhibit the formation of joints in the adjacent digits. These data suggest that the role of GDF-5 in joint formation is the control of growth and differentiation of the cartilage of the epiphyseal regions of the phalanges rather than accounting for the differentiation of the sinovial joint tissues. The interdigital mesoderm in spite of its potential to form ectopic digits with their tendinous apparatus failed to form either ectopic cartilages or ectopic tendons after the implantation of GDF-5 beads in the stages preceding cell death. At difference with other BMPs, GDF-5 exhibited only a weak cell death promoting effect. The BMP antagonist Noggin binds to GDF-5 and is able to inhibit all the observed effects of this growth factor in vivo. Potential interactions of GDF-5 with other signals involved in digits morphogenesis were also explored. BMP-7 regulates negatively the expression of gdf-5 gene in the joint forming regions and local treatment with Noggin induces the ectopic expression of gdf-5 in the interdigital mesoderm. Retroviral-induced misexpression of Indian or Sonic Hedgehog genes in the developing digits leads to the formation of digits without joints in which gdf-5 expression occurs throughout the entire perichondrial surface. In conclusion, this study indicates that GDF-5 is a signal regulated by other BMPs which controls the growth and differentiation of the epiphyses of the digital cartilages acting in close relationship with Hedgehog signaling.

Mechanisms of digit formation: Human malformation syndromes tell the story

“…Bone morphogenetic protein (BMP) signaling is a major positive regulator of chondrogenesis (Duprez et al, 1996;Francis-West et al, 1996;Merino et al, 1999;Pizette and Niswander, 2000). BMPs and the closely related growth and differentiation factors (Gdfs) belong to the transforming growth factor-beta (Tgfb) superfamily and in mammals comprise 21 members.…”

Accelerated hypertrophic chondrocyte kinetics in GDF‐7 deficient murine tibial growth plates

“…While a role for GDF-7/BMP-12 in chondrocyte biology and growth plate kinetics has, to our knowledge, not been reported in the literature, there is extensive evidence implicating the related molecule, GDF-5, in chondrocyte differentiation and maturation. [1][2][3][4][5][6][7] Most recently, 5-week-old female mice deficient in GDF-5 were shown to have the opposite phenotype in the proximal tibial growth plate relative to that seen in the present study with GDF-7 deficient mice of the same age and sex. 8 Compared to control growth plates, the physes from GDF-5 À/À animals had slower growth rates that were associated with a longer hypertrophic phase duration, whereas, in our current study, GDF-7 deficient growth plates had faster growth rates that were associated with a shorter hypertrophic phase duration.…”

“…[1][2][3][4][5][6][7] Five-week-old female mice deficient in one of these molecules, GDF-5, have additionally been shown to exhibit a significant reduction in proximal tibial growth rate due to a lengthened hypertrophic phase duration. 8 Most recently, Miyamoto and colleagues have demonstrated that Gdf5 appears to be a susceptibility gene for osteoarthritis, and that decreased Gdf5 expression may be associated with the development of this degenerative joint disease.…”

Canonical Wnt signaling activity during synovial joint development

“…This suggestive conclusion is partially supported by a recent cell fate study that used Gdf5-Cre mice mated with ROSA-LacZ mice (Koyama et al 2008). The growth differentiation factor Gdf5 is restrictively expressed in the interzone cells at the initial stage of the joint formation (Merino et al 1999;Storm and Kingsley 1999). Indeed, the Gdf5-Cre/ROSA-LacZ reporter-expressing cells were originally found in the joint interzone cells and subsequently predominant in articulating layers and accessory joint tissues (Koyama et al 2008).…”