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 mice homozygous for a null mutation of the PTH-related peptide (PTHrP) gene was due in part to reduced proliferation and aberrant differentiation of growth plate chondrocytes. In the present study we have extended those observations by examining chondrocytes for evidence of PTH/PTHrP receptor expression, proliferation, and programmed cell death. Receptor messenger RNA and protein were expressed in chondrocytes in the resting and proliferative zones of both wild-type and mutant mice. In normal animals, expression was abundant in the area of transition between proliferative and hypertrophic chondrocytes and absent from cells in the lower hypertrophic region. On the other hand, the hypertrophic zone in mutant mice contained nonhypertrophic chondrocytes, which exhibited characteristics of proliferating cells, including PTH/PTHrP receptor expression, [3H]thymidine incorporation, and expression of proliferating cell nuclear antigen. In contrast to the situation in normal animals, some cells adjacent to the zone of vascular invasion in mutant growth plates showed biochemical and morphological evidence of programmed cell death. In addition to these alterations in the maturation of growth plate chondrocytes, homozygous mutants demonstrated signs of aberrant differentiation of periosteal precursor cells. In some specimens, clusters of chondrocytes embedded in a cartilaginous matrix were observed between the layers of periosteal osteoblasts and the bony collar in the sterna and tibiae of mice homozygous for a null mutation of the PTHrP gene. Taken together, these observations indicate that PTHrP plays a pivotal role in the orderly progression of chondrocytes through 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.
Amizuka
N
N
Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Canada.
Henderson
J E
JE
Hoshi
K
K
Warshawsky
H
H
Ozawa
H
H
Goltzman
D
D
Karaplis
A C
AC
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D002358:Cartilage, Articular / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division; D003094:Collagen / Q000032:analysis / Q000096:biosynthesis; D017353:Gene Deletion; D006132:Growth Plate; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000473:pathology / Q000648:ultrastructure; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000096:biosynthesis; D044162:Parathyroid Hormone-Related Protein; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000032:analysis / Q000096:biosynthesis; D013936:Thymidine / Q000378:metabolism
D015415:Biomarkers; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D003094:Collagen; D013936:Thymidine