The PTH/PTHrP receptor binds to two ligands with distinct functions: the calcium-regulating hormone, parathyroid hormone (PTH), and the paracrine factor, PTH-related protein (PTHrP). Each ligand, in turn, is likely to activate more than one receptor. The functions of the PTH/PTHrP receptor were investigated by deletion of the murine gene by homologous recombination. Most PTH/PTHrP receptor (-/-) mutant mice died in mid-gestation, a phenotype not observed in PTHrP (-/-) mice, perhaps because of the effects of maternal PTHrP. Mice that survived exhibited accelerated differentiation of chondrocytes in bone, and their bones, grown in explant culture, were resistant to the effects of PTHrP and Sonic hedgehog. These results suggest that the PTH/PTHrP receptor mediates the effects of Indian Hedgehog and PTHrP on chondrocyte differentiation.

Vitamin D, the major steroid hormone that controls mineral ion homeostasis, exerts its actions through the vitamin D receptor (VDR). The VDR is expressed in many tissues, including several tissues not thought to play a role in mineral metabolism. Studies in kindreds with VDR mutations (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia. Alopecia, which is not a feature of vitamin D deficiency, is seen in some kindreds. We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain. Despite known expression of the VDR in fetal life, homozygous mice are phenotypically normal at birth and demonstrate normal survival at least until 6 months. They become hypocalcemic at 21 days of age, at which time their parathyroid hormone (PTH) levels begin to rise. Hyperparathyroidism is accompanied by an increase in the size of the parathyroid gland as well as an increase in PTH mRNA levels. Rickets and osteomalacia are seen by day 35; however, as early as day 15, there is an expansion in the zone of hypertrophic chondrocytes in the growth plate. In contrast to animals made vitamin D deficient by dietary means, and like some patients with VDDR II, these mice develop progressive alopecia from the age of 4 weeks.1,25-Dihydroxyvitamin D is the major steroid hormone that plays a role in mineral ion homeostasis. Its actions are thought to be mediated by a nuclear receptor, the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor and interacts with specific DNA sequences on target genes. The VDR is evolutionarily well conserved and is expressed early in development in amphibians (1), mammals (2), and birds (3, 4). As well as being expressed in the intestine, the skeleton, and the parathyroid glands, the VDR is found in several tissues not thought to play a role in mineral ion homeostasis (5). Its precise functions in these tissues, as well as its developmental role, remain unclear.Insights into the physiological actions of 1,25-dihydroxyvitamin D have been obtained from studies in vitamin Ddeficient animals (6-10) as well as in humans with VDR mutations (11,12). These investigations have demonstrated that 1,25-dihydroxyvitamin D plays an important role in intestinal calcium absorption and that animals lacking the active hormone or its nuclear receptor develop hypocalcemia, rickets, osteomalacia, and hyperparathyroidism. Although skin changes similar to psoriasis have been observed in vitamin D-deficient rats (13), the alopecia observed in some kindreds with mutant VDRs has not been observed in vitamin D deficiency.We have generated an animal model of vitamin Ddependent rickets type II (VDDR II) by targeted ablation of DNA encoding the second zinc finger of the DNA-binding domain of the VDR. The resultant animals are phenotypically normal at birth; however, they develop hypocalcemia, hyperparathyroidism, and alopecia within the first month of life. MATERIALS AND METHODSGenera...