LETHAL SKELETAL DYSPLASIA FROM TARGETED DISRUPTION OF THE PARATHYROIDHORMONE-RELATED PEPTIDE GENE

The parathyroid hormone-related peptide (PTHrP) gene was disrupted in murine embryonic stem cells by homologous recombination, and the null allele was introduced into the mouse germ line. Mice homozygous for th e PTHrP null mutation died postnatally, probably from asphyxia, and ex hibited widespread abnormalities of endochondral bone development. His tological examination revealed a diminution of chondrocyte proliferati on, associated with premature maturation of chondrocytes and accelerat ed bone formation. Analysis of earlier developmental stages revealed t hat disturbance in cartilage growth preceded abnormal endochondral bon e formation. There were no morphological abnormalities apparent in oth er tissues. These results provide direct evidence implicating PTHrP in normal skeletal development and serve to emphasize its potential invo lvement in human osteochondrodysplasias.