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Partial Rescue of PTH/PTHrP Receptor Knockout Mice by Targeted Expression of the Jansen Transgene

Molecular Endocrinology, Max-Planck-Institute for Biochemistry, Martinsried 85152, Germany; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School (E.S., H.J.), Boston, Massachusetts 02114; and Institute of Animal Physiology, Ludwig-Maximilian University of Munich (R.G.E.), Munich 80539, Germany

The homozygous ablation of the gene encoding the PTH/PTHrP receptor (PPR^-/-) leads to early lethality and limited developmental defects, including an acceleration of chondrocyte differentiation. In contrast to the findings in homozygous PTHrP-ablated (PTHrP^-/-) animals, these PPR^-/- mice show an increase in cortical bone, a decrease in trabecular bone, and a defect in bone mineralization. Opposite observations are made in Jansen’s metaphyseal chondrodysplasia, a disorder caused by constitutively active PPR mutants, and in transgenic animals expressing one of these receptor mutants (HKrk-H223R) under control of the type 1(I) collagen promoter. Expression of the Jansen transgene under the control of the type 1(II) collagen promoter was, furthermore, shown to delay chondrocyte differentiation and to prevent the dramatic acceleration of chondrocyte differentiation in PTHrP^-/- mice, thus rescuing the early lethality of these animals. In the present study we demonstrated that the type 1(II) collagen promoter Jansen transgene restored most of the bone abnormalities in PPR^-/- mice, but did not prevent their perinatal lethality. These findings suggested that factors other than impaired gas exchange due to an abnormal rib cage contribute to the early death of PPR^-/- mice.

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