title: Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene.
abstract: 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 alpha1(I) collagen promoter. Expression of the Jansen transgene under the control of the type alpha1(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 alpha1(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.
authors.affiliation: Molecular Endocrinology, Max-Planck-Institute for Biochemistry, Martinsried 85152, Germany.
authors.forename: D W
authors.initials: DW
authors.lastname: Soegiarto
authors.forename: S
authors.initials: S
authors.lastname: Kiachopoulos
authors.forename: E
authors.initials: E
authors.lastname: Schipani
authors.forename: H
authors.initials: H
authors.lastname: Jüppner
authors.forename: R G
authors.initials: RG
authors.lastname: Erben
authors.forename: B
authors.initials: B
authors.lastname: Lanske
mesh_terms: D000818:Animals; D019902:Chondrocytes / Q000502:physiology; D024043:Collagen Type II / Q000235:genetics; D004622:Embryo, Mammalian / Q000473:pathology; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015870:Gene Expression; D018390:Gene Targeting; D006132:Growth Plate / Q000378:metabolism; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D013977:Tibia / Q000196:embryology / Q000473:pathology; D019076:Transgenes
chemical_list: D024043:Collagen Type II; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone