Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene.

TLDR

The PTHrP gene was knocked out in mouse embryonic stem cells via homologous recombination and transmitted to the germ line. Homozygous PTHrP‑null mice died after birth, likely from asphyxia, and displayed widespread defects in endochondral bone development due to reduced chondrocyte proliferation, premature maturation, and accelerated bone formation, with no other tissue abnormalities, underscoring PTHrP’s essential role in skeletal development and its relevance to human osteochondrodysplasias.

Abstract

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 the PTHrP null mutation died postnatally, probably from asphyxia, and exhibited widespread abnormalities of endochondral bone development. Histological examination revealed a diminution of chondrocyte proliferation, associated with premature maturation of chondrocytes and accelerated bone formation. Analysis of earlier developmental stages revealed that disturbance in cartilage growth preceded abnormal endochondral bone formation. There were no morphological abnormalities apparent in other tissues. These results provide direct evidence implicating PTHrP in normal skeletal development and serve to emphasize its potential involvement in human osteochondrodysplasias.