Atf4 is a leucine zipper-containing transcription factor that activates 
osteocalcin (Ocn) in osteoblasts and indian hedgehog (Ihh) in chondrocytes. The 
relative contribution of Atf4 in chondrocytes and osteoblasts to the regulation 
of skeletal development and bone formation is poorly understood. Investigations 
of the Atf4(-/-);Col2a1-Atf4 mouse model, in which Atf4 is selectively 
overexpressed in chondrocytes in an Atf4-null background, demonstrate that 
chondrocyte-derived Atf4 regulates osteogenesis during development and bone 
remodeling postnatally. Atf4 overexpression in chondrocytes of the 
Atf4(-/-);Col2a1-Atf4 double mutants corrects the reduction in stature and limb 
in Atf4(-/-) embryos and rectifies the decrease in Ihh expression, Hh signaling, 
proliferation and accelerated hypertrophy that characterize the Atf4(-/-) 
developing growth plate cartilages. Unexpectedly, this genetic manipulation also 
restores the expression of osteoblastic marker genes, namely Ocn and bone 
sialoprotein, in Atf4(-/-) developing bones. In Atf4(-/-);Col2a1-Atf4 adult 
mice, all the defective bone parameters found in Atf4(-/-) mice, including bone 
volume, trabecular number and thickness, and bone formation rate, are rescued. 
In addition, the conditioned media of ex vivo cultures from wild-type or 
Atf4(-/-);Col2a1-Atf4, but not Atf4(-/-) cartilage, corrects the differentiation 
defects of Atf4(-/-) bone marrow stromal cells and Ihh-blocking antibody 
eliminates this effect. Together, these data indicate that Atf4 in chondrocytes 
is required for normal Ihh expression and for its paracrine effect on osteoblast 
differentiation. Therefore, the cell-autonomous role of Atf4 in chondrocytes 
dominates the role of Atf4 in osteoblasts during development for the control of 
early osteogenesis and skeletal growth.