Activation of the parathyroid hormone/parathyroid hormone related peptide common receptor (PPR) modulates specific regional, temporal and signal transduction events in an avian sternal model

Cells can change shape, size, position, and gene expression, particularly during development. For example, chondroblasts and osteoblasts embryo-logically may differentiate from the same mesenchymal population during skeletal development (Jimenez et al., 2001). Endochondral ossification of primary hyaline cartilage forms the base of the skull (chondrocranium). Proper development and growth of this cartilage is essential for normal phenotype of the craniofacial complex. Genetic diseases that affect expression of collagen molecules within the developing cartilage matrix can lead to osteochondrodysplasias, affecting cartilage and bone. Mutations in the type X collagen gene have been identified in the Schmid type of osteochondrodysplasias (Williams and Jimenez 1995). Other genetic defects can result in a chondrodysplasia phenotype. Jansen's metaphyseal chondrodysplasia results from a constitutively active parathyroid hormone receptor (PPR) caused by a point mutation (Schipani, et al. 1995). The patients with this disease have disrupted long bone formation and craniofacial abnormalities (McKusick., 1972). The parathyroid hormone receptor transduces signals that appear to regulate chondrocyte differentiation (Juppner et al., 1991; Abou-Samra et al., 1992). Although this receptor appears critical for proper development and growth of cartilage, the signal transduction and downstream effects promoted from its activation are poorly understood. Therefore, the objective of this dissertation was to investigate the effects of the PPR ligand, PTH, in a chondrogenic model, using phenotypes of cartilaginous differentiation as an endpoint.