Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.
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...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.