Bone morphogenetic proteins (BMPs) constitute a large family of secreted si
gnals involved in the formation of the skeleton but the specific function o
f 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 t
he induction and growth of the appendicular cartilages, the determination o
f joint forming regions, and the establishment of tendons. Here, we have st
udied the function of GDF-5 in digit skeletogenesis by analyzing the effect
s of its local administration in the developing autopod of embryonic chick
and the regulation of its pattern of gene expression by other signals invol
ved in digit morphogenesis. As reported in the mouse, the gdf-5 gene exhibi
ts a precise distribution in the joint-forming regions of the developing ch
icken digital rays. GDF-5 beads implanted at the tip of the digits promote
intense cartilage growth and fail to induce morphological or molecular sign
s 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 dif
ferentiation of the cartilage of the epiphyseal regions of the phalanges ra
ther 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 preced
ing 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 i
s able to inhibit all the observed effects of this growth factor in vivo. P
otential interactions of GDF-5 with other signals involved in digits morpho
genesis were also explored. BMP-7 regulates negatively the expression of gd
f-5 gene in the joint forming regions and local treatment with Noggin induc
es 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 expre
ssion occurs throughout the entire perichondrial surface. In conclusion, th
is study indicates that GDF-5 is a signal regulated by other BMPs which con
trols the growth and differentiation of the epiphyses of the digital cartil
ages acting in close relationship with Hedgehog signaling. (C) 1999 Academi
c Press.