DEFECTIVE BONE-FORMATION IN KROX-20 MUTANT MICE

Endochondral ossification is the prevalent mode of vertebrate skeleton formation; it starts during embryogenesis when cartilage models of lo ng bones develop central regions of hypertrophy which are replaced by bony trabeculae and bone marrow. Although several transcription factor s have been implicated in pattern formation in the limbs and axial ske leton, little is known about the transcriptional regulations involved in bone formation. We have created a null allele in the mouse Krox-20 gene, which encodes a zinc finger transcription factor, by in frame in sertion of the E. coli lacZ gene and shown that hindbrain segmentation and peripheral nerve myelination are affected in Krox-20(-/-) embryos . We report here that Krox-20 is also activated in a subpopulation of growth plate hypertrophic chondrocytes and in differentiating osteobla sts and that its disruption severely affects endochondral ossification . Krox-20(-/-) mice develop skeletal abnormalities including a reduced length and thickness of newly formed bones, a drastic reduction of ca lcified trabeculae and severe porosity. The periosteal component to bo ne formation and calcification does not appear to be affected in the h omozygous mutant suggesting that the major role for Krox-20 is to be f ound in the control of the hypertrophic chondrocyte-osteoblast interac tions leading to endosteal bone formation.