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.

Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

“…They showed delayed mineralization, decelerated chondrocyte maturation in skeletal segments that are formed by the endochondral process, and prolonged presence of hypertrophic chondrocytes with delay of vascular invasion (Schipani et al, 1997b). The transgene also corrects most of the bone abnormalities in PTHR1 knockout mice, although the PTHR1 null mice with the transgene still die perinatally (Soegiarto et al , 2001). Expression of the same CAM in osteoblasts by placing its expression under the control of the type I collagen promoter showed that both the osteoblast and osteoclast numbers were increased, suggesting that PTH activation of PTHR1 in osteoblasts increase both bone-forming and bone-resorbing activities (Calvi et al , 2001).…”

Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis

“…An increase in levels of deoxypyridinoline in amniotic fluid of these mice suggests that increased bone resorption might contribute to the hypercalcemia of these mice (12). Further, in fetal mice missing the PTH receptor, expression of a constitutively active PTH receptor only in osteoblastic cells increased blood calcium (13). Here we examine the role of PTH action on bone in normal fetal calcium homeostasis.…”

Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor

“…In contrast, mice expressing a constitutively active PTH/PTHrP receptor ( Jansen transgene) under the collagen (α1) type 2 promoter have been shown to exhibit a delay in chondrocyte differentiation, rescuing the massive hypertrophy in chondrocytes lacking PTHrP [13–15]. To test whether the Jansen transgene could rescue the loss of the growth plate in Col2-cre ER * ; Ihh d/d mice after birth, we generated Col2a1-Cre ER * ; Ihh fl/fl , J double mutants and injected them at P0 with tamoxifen to generate mice lacking Ihh, but expressing the Jansen receptor in postnatal chondrocytes.…”