The cellular and molecular mechanisms that underlie age-dependent osteoporosis, the most common disease in the Western Hemisphere, are poorly understood in part due to the lack of appropriate animal models in which to study disease progression. Here, we present a model that shows many similarities to the human disease. Sca-1, well known for its expression on hematopoietic stem cells, is present on a subset of bone marrow stromal cells, which potentially include mesenchymal stem cells. Longitudinal studies showed that Sca-1 ؊/؊ mice undergo normal bone development but with age exhibit dramatically decreased bone mass resulting in brittle bones. In vivo and in vitro analyses demonstrated that Sca-1 is required directly for the self-renewal of mesenchymal progenitors and indirectly for the regulation of osteoclast differentiation. Thus, defective mesenchymal stem or progenitor cell self-renewal may represent a previously uncharacterized mechanism of age-dependent osteoporosis in humans.O steoporosis is a multifactorial, age-related metabolic bone disease characterized by low bone mineral density (BMD) and the deterioration of the microarchitecture of cancellous bone, leading to enhanced bone fragility and increased risk of fracture (1). Type I osteoporosis, also called postmenopausal osteoporosis because it primarily affects postmenopausal women, is characterized by increased bone turnover and accelerated cancellous bone loss, increasing the risk of vertebral fracture. Type II osteoporosis, or age-related͞dependent osteoporosis, affects older women and men and its origins are far less understood than postmenopausal osteoporosis. Although type II osteoporosis is not accompanied by increased bone turnover, it leads to increased risk of hip fracture and has a greater mortality and morbidity than type I osteoporosis.Type I and II osteoporosis are thought to result from dysregulated bone remodeling during aging. Normal bone remodeling requires an exquisite balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteoblasts are mesenchymal cells that originate from a multipotential precursor, often referred to as the mesenchymal stem cell (MSC), which also gives rise to other lineages such as adipocytes, chondrocytes, and muscle (2, 3). By contrast, osteoclasts differentiate from hematopoietic monocyte͞macrophage precursors (4).Stem cell antigen 1 (Sca-1; also known as Ly-6A) is an 18-kDa glycosyl phosphatidylinositol-anchored cell surface protein of the Ly-6 gene family expressed by hematopoietic stem cells (HSCs), skeletal muscle stem cells, mammary epithelial stem cells, subsets of hematopoietic progenitors, lymphocytes and macrophages, and a subpopulation of bone marrow (BM) stromal cells including osteoblasts (5-11). Sca-1 Ϫ/Ϫ mice exhibit defects in T cell signaling (12) and HSC self-renewal (13).Here, we report that Sca-1 Ϫ/Ϫ mice also model human agerelated (type II) osteoporosis with reduced BMD and increased susceptibility to fractures. Unlike type I osteoporosis, which results from an...
PurposeAutosomal recessive non-syndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity with reported mutations in 58 different genes. This study was designed to detect deafness causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).MethodsAfter excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador and Puerto Rico to screen for mutations in all known ARNSD genes.ResultsWe detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%) and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes suggesting founder effects.ConclusionWe report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.
The transforming growth factor beta 1 (TGF beta 1) signalling pathway is important in embryogenesis and has been implicated in hereditary haemorrhagic telangiectasia (HHT), atherosclerosis, tumorigenesis and immunomodulation. Therefore, identification of factors which modulate TGF beta 1 bioactivity in vivo is important. On a mixed genetic background, approximately 50% Tgfb1-/- conceptuses die midgestation from defective yolk sac vasculogenesis. The other half are developmentally normal but die three weeks postpartum. Intriguingly, the vascular defects of Tgfb1-/- mice share histological similarities to lesions seen in HHT patients. It has been suggested that dichotomy in Tgfb1-/- lethal phenotypes is due to maternal TGF beta 1 rescue of some, but not all, Tgfb1-/- embryos12. Here we show that the Tgfb1-/- phenotype depends on the genetic background of the conceptus. In NIH/Ola, C57BL/6J/Ola and F1 conceptuses, Tgfb1-/- lethality can be categorized into three developmental classes. A major codominant modifier gene of embryo lethality was mapped to proximal mouse chromosome 5, using a genome scan for non-mendelian distribution of alleles in Tgfb1-/- neonatal animals which survive prenatal lethality. This gene accounts for around three quarters of the genetic effect between mouse strains and can, in part, explain the distribution of the three lethal phenotypes. This approach, using neonatal DNA samples, is generally applicable to identification of loci that influence the effect of early embryonic lethal mutations, thus furthering knowledge of genetic interactions that occur during early mammalian development in vivo.
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.