Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development

Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) b ind to and activate the same PTH/PTHrP receptor. Deletion of either the PTH rP gene or the PTH/PTHrP receptor gene leads to acceleration of differentia tion of growth plate chondrocytes. To explore further the functional relati onships of PTHrP and the PTH/PTHrP receptor, bones of knockout mice were an alyzed early in development, and the phenotypes of double-knockout mice wer e characterized. One early phenotype is shared by both knockouts. Normally, the first chondr ocytes to become hypertrophic are located in the centers of long bones; thi s polarity is greatly diminished in both these knockouts. The PTH/PTHrP rec eptor-deficient (PTH/PTHrP-R-/-) mice exhibited 2 unique phenotypes not sha red by the PTHrP(-/-) mice. During intramembranous bone formation in the sh afts of long bones, only the PTH/PTHrP-R-/- bones exhibit a striking increa se in osteoblast number and matrix accumulation. Furthermore, the PTH/PTHrP -R-/- mice showed a dramatic decrease in trabecular bone formation in the p rimary spongiosa and a delay in vascular invasion of the early cartilage mo del. In the double-homozygous knockout mice, the delay in vascular invasion did not occur. Thus, PTHrP must slow vascular invasion by a mechanism inde pendent of the PTH/PTHrP receptor.