Absence of functional type 1 parathyroid hormone (PTH)/PTH-related proteinreceptors in humans is associated with abnormal breast development and tooth impaction

Recent studies in transgenic mice have demonstrated that PTH-related protei n (PTHrP), signaling through the type 1 PTH/PTHrP receptor (PTHR1), regulat es endochondral bone development and epithelial-mesenchymal interactions du ring the formation of the mammary glands and teeth. Recently, it has been s hown that loss-of-function mutations in the PTHR1 gene result in a rare, le thal form of dwarfism known as Blomstrand chondrodysplasia. These patients suffer from severe defects in endochondral bone formation, but abnormalitie s in breast and tooth development have not been reported. To ascertain whet her PTHrP signaling was important to human breast and tooth development, we studied two fetuses with Blomstrand chondrodysplasia. These fetuses lack n ipples and breasts. Developing teeth were present, but they were severely i mpacted within the surrounding alveolar bone, leading to distortions in the ir architecture and orientation. Compatible with the involvement of PTHR1 a nd PTHrP in human breast and tooth morphogenesis, both were expressed withi n the developing breasts and teeth of normal human fetuses. Therefore, impa irment of the PTHrP/PTHR1 signaling pathway in humans is associated with se vere abnormalities in tooth and breast development. In addition to regulati ng human bone formation, this signaling pathway is also necessary for the n ormal development of the human breast and tooth.