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Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene
A C Karaplis1, A Luz, J Glowacki
1Endocrine Unit, Massachusetts General Hospital, Boston 02114.
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.
Insights
Parathyroid hormone-related peptide (PTHrP) is crucial for skeletal development. Disrupting the PTHrP gene in mice caused severe bone abnormalities and postnatal death, highlighting its role in cartilage growth and bone formation.
Area of Science:
- Skeletal Biology
- Developmental Biology
- Genetics
Background:
- Parathyroid hormone-related peptide (PTHrP) is a key signaling molecule involved in development.
- Its precise role in endochondral ossification and skeletal development requires further elucidation.
Purpose of the Study:
- To investigate the function of PTHrP in skeletal development using a gene knockout mouse model.
- To determine the consequences of PTHrP deficiency on chondrocyte proliferation, maturation, and endochondral bone formation.
Main Methods:
- Gene disruption of the parathyroid hormone-related peptide (PTHrP) gene in murine embryonic stem cells via homologous recombination.
- Generation of a PTHrP null allele and introduction into the mouse germ line.
- Histological and developmental analyses of homozygous PTHrP null mutant mice.
Main Results:
- Mice homozygous for the PTHrP null mutation exhibited embryonic lethality or postnatal death, likely due to asphyxia.
- Widespread abnormalities in endochondral bone development were observed, including reduced chondrocyte proliferation and premature chondrocyte maturation.
- Disturbances in cartilage growth preceded abnormal endochondral bone formation, with no other apparent tissue abnormalities.
Conclusions:
- PTHrP is essential for normal endochondral skeletal development in mice.
- PTHrP deficiency leads to severe defects in cartilage growth and bone formation.
- These findings suggest a potential role for PTHrP in human osteochondrodysplasias.