PARATHYROID HORMONE-RELATED PROTEIN IS REQUIRED FOR TOOTH ERUPTION

Parathyroid hormone (PTH)-related protein (PTHrP)-knockout mice die at birth with a chondrodystrophic phenotype characterized by premature c hondrocyte differentiation and accelerated bone formation, whereas ove rexpression of PTHrP in the chondrocytes of transgenic mice produces a delay in chondrocyte maturation and endochondral ossification, Replac ement of PTHrP expression in the chondrocytes of PTHrP-knockout mice u sing a procollagen II-driven transgene results in the correction of th e lethal skeletal abnormalities and generates animals that are effecti vely PTHrP-null in all sites other than cartilage. These rescued PTHrP -knockout mice survive to at least 6 months of age but are small in st ature and display a number of developmental defects, including cranial chondrodystrophy and a failure of tooth eruption. Teeth appear to dev elop normally but become trapped by the surrounding bone and undergo p rogressive impaction. Localization of PTHrP mRNA during normal tooth d evelopment by in situ hybridization reveals increasing levels of expre ssion in the enamel epithelium before the formation of the eruption pa thway. The type I PTH/PTHrP receptor is expressed in both the adjacent dental mesenchyme and in the alveolar bone. The replacement of PTHrP expression in the enamel epithelium with a keratin 14-driven transgene corrects the defect in bone resorption and restores the normal progra m of tooth eruption. PTHrP therefore represents an essential signal in the formation of the eruption pathway.