PROGRAMMED CELL-DEATH OF CHONDROCYTES AND ABERRANT CHONDROGENESIS IN MICE HOMOZYGOUS FOR PARATHYROID HORMONE-RELATED PEPTIDE GENE DELETION

In previous work we showed that the chondrodysplastic phenotype of mic e homozygous for a null mutation of the PTH-related peptide (PTHrP) ge ne was due in part to reduced proliferation and aberrant differentiati on of growth plate chondrocytes. In the present study we have extended those observations by examining chondrocytes for evidence of PTH/PTHr P receptor expression, proliferation, and programmed cell death. Recep tor messenger RNA and protein were expressed in chondrocytes in the re sting and proliferative zones of both wild-type and mutant mice. In no rmal animals, expression was abundant in the area of transition betwee n proliferative and hypertrophic chondrocytes and absent from cells in the lower hypertrophic region. On the other hand, the hypertrophic zo ne in mutant mice contained nonhypertrophic chondrocytes, which exhibi ted characteristics of proliferating cells, including PTH/PTHrP recept or expression, [H-3]thymidine incorporation, and expression of prolife rating cell nuclear antigen. In contrast to the situation in normal an imals, some cells adjacent to the zone of vascular invasion in mutant growth plates showed biochemical and morphological evidence of program med cell death. In addition to these alterations in the maturation of growth plate chondrocytes, homozygous mutants demonstrated signs of ab errant differentiation of periosteal precursor cells. In some specimen s, clusters of chondrocytes embedded in a cartilaginous matrix were ob served between the layers of periosteal osteoblasts and the bony colla r in the sterna and tibiae of mice homozygous for a null mutation of t he PTHrP gene. Taken together, these observations indicate that PTHrP plays a pivotal role in the orderly progression of chondrocytes throug h stages of proliferation, differentiation, and programmed cell death in the epiphyseal growth plate and may also facilitate the commitment of precursors to cells of the chondrocytic or osteoblastic lineages.