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...

Soluble transforming growth factor-␤ (TGF-␤)/bone morphogenetic protein (BMP)-binding proteins are widely distributed in mammalian tissues and control cytokine access to membrane signaling receptors. The serum and bone-resident glycoprotein ␣2-HS-glycoprotein/fetuin (ASHG) binds to TGF-␤/BMP cytokines and blocks TGF-␤1 binding to cell surface receptors. Therefore, we examined bone growth and remodeling phenotypes in ASHG-deficient mice. The skeletal structure of Ahsg ؊/؊ mice appeared normal at birth, but abnormalities were observed in adult Ahsg ؊/؊ mice. Maturation of growth plate chondrocytes was impaired, and femurs lengthened more slowly between 3 and 18 months of age in Ahsg ؊/؊ mice. However, bone formation was increased in Ahsg ؊/؊ mice as indicated by greater cortical thickness, accelerated trabecular bone remodeling, and increased osteoblast numbers on bone surfaces. The normal age-related increase in cortical thickness and bone mineral density was accelerated in Ahsg ؊/؊ mice and was associated with increased energy required to fracture. Bone formation in response to implanted BMP cytokine extended further from the implant in Ahsg ؊/؊ compared with Ahsg ؉/؉ mice, confirming the interaction between ASHG and TGF-␤/BMP cytokines in vivo. Our results demonstrate that ASHG blocks TGF-␤-dependent signaling in osteoblastic cells, and mice lacking ASHG display growth plate defects, increased bone formation with age, and enhanced cytokine-dependent osteogenesis.