Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1/Ly-6A null mice

Abstract

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...

Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment

“…Experimental evidence to support the notion that plastic-nonadherent bone marrow cells are osteoprogenitors was originally reported by two independent research groups using in vivo transplantation studies [17,18], supported by substantial in vitro data [21][22][23][24][25]. Our previously published data suggested that nonadherent marrow cells are more potent osteoprogenitors than MSCs, indeed the most potent transplantable marrow osteoprogenitor, after intravenous infusion.…”

Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity

“…Stem cell antigen 1 (Sca-1), a marker previously described on hematopoietic stem cells, also has been described on mesenchymal osteoprogenitor cells and is directly required for their self-renewal. (21)(22)(23) In addition, new evidence suggests that the majority of MSCs are not actually located within the bone marrow but rather within the bone tissue itself or, more specifically, within the vascular system of the bone. (24)(25)(26) Therefore, employing fluorescence-activated cell sorting (FACS) for Sca-1 on cells purified from murine bone tissue following a rigorous depletion of hematopoietic cells results in two populations enriched for mesenchymal progenitor cells: highly proliferative Sca-1 þ MSCs, which have been shown to exhibit adipogenic, chondrogenic, and osteogenic potential, and Sca-1 À CD51 þ cells that are more committed toward the osteogenic lineage and hence referred to as osteoprogenitor cells.…”

Functional characterization of human osteoclast inhibitory peptide-1 (OIP-1/hSca) gene promoter

“…It has also been suggested that GPI-anchored proteins transmit signals to the cell interior by interacting with non-receptor type tyrosine kinases p56 lck and p59 fyn (Stefanova et al, 1991). Ly-6A (Sca-1) knock-out mice demonstrated that bone mineral density and bone mineral content in Sca-1 null mice were significantly lower than wild type mice at 12 months period (Bonyadi et al, 2003). These studies implicate an essential role for Ly-6 gene family in normal bone remodeling.…”