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

J Clin Invest. 1999 Aug;104(4):399-407. doi: 10.1172/JCI6629.


Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) bind to and activate the same PTH/PTHrP receptor. Deletion of either the PTHrP gene or the PTH/PTHrP receptor gene leads to acceleration of differentiation of growth plate chondrocytes. To explore further the functional relationships of PTHrP and the PTH/PTHrP receptor, bones of knockout mice were analyzed early in development, and the phenotypes of double-knockout mice were characterized. One early phenotype is shared by both knockouts. Normally, the first chondrocytes to become hypertrophic are located in the centers of long bones; this polarity is greatly diminished in both these knockouts. The PTH/PTHrP receptor-deficient (PTH/PTHrP-R(-/-)) mice exhibited 2 unique phenotypes not shared by the PTHrP(-/-) mice. During intramembranous bone formation in the shafts of long bones, only the PTH/PTHrP-R(-/-) bones exhibit a striking increase in osteoblast number and matrix accumulation. Furthermore, the PTH/PTHrP-R(-/-) mice showed a dramatic decrease in trabecular bone formation in the primary spongiosa and a delay in vascular invasion of the early cartilage model. In the double-homozygous knockout mice, the delay in vascular invasion did not occur. Thus, PTHrP must slow vascular invasion by a mechanism independent of the PTH/PTHrP receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Development / genetics*
  • Bone Development / physiology*
  • Bone and Bones / abnormalities*
  • Bone and Bones / blood supply
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Osteoblasts / pathology
  • Parathyroid Hormone-Related Protein
  • Phenotype
  • Pregnancy
  • Proteins / genetics*
  • Proteins / physiology*
  • Receptor, Parathyroid Hormone, Type 1
  • Receptors, Parathyroid Hormone / genetics*
  • Receptors, Parathyroid Hormone / physiology*


  • Parathyroid Hormone-Related Protein
  • Proteins
  • Receptor, Parathyroid Hormone, Type 1
  • Receptors, Parathyroid Hormone