Bone remodeling involves the resorption of bone by osteoclasts and the synthesis of bone matrix by osteoblasts. Receptor activator of NF-kB ligand (RANKL, also known as ODF and OPGL), a member of the tumor necrosis factor (TNF) family, triggers osteoclastogenesis by forming a complex with its receptor, RANK. We have determined the crystal structure of the extracellular domain of mouse RANKL at 2.2-Å resolution. The structure reveals that the RANKL extracellular domain is trimeric, which was also shown by analytical ultracentrifugation, and each subunit has a ␤-strand jellyroll topology like the other members of the TNF family. A comparison of RANKL with TNF␤ and TNF-related apoptosis-inducing ligand (TRAIL), whose structures were determined to be in the complex form with their respective receptor, reveals conserved and specific features of RANKL in the TNF superfamily and suggests the presence of key residues of RANKL for receptor binding.Bone remodeling involves the resorption of bone by osteoclasts and the synthesis of bone matrix by osteoblasts (1). Osteoclasts and osteoblasts arise from distinct cell lineages and maturation processes. Osteoclasts differentiate from hematopoietic precursors of the monocyte/macrophage lineage, whereas osteoblasts arise from mesenchymal stem cells. Osteoclasts are formed in vitro from osteoclast progenitors by coculturing with osteoblasts or bone marrow stromal cells in the presence of stimulators, including colony-stimulating factor-1 (CSF-1 or M-CSF), interleukin (IL)-6, 1 IL-11, parathyroid hormone, prostaglandin E 2 , and vitamin D 3 . The activation of osteoclasts is regulated by osteoblasts/stromal cells through a mechanism of cell-to-cell interaction with osteoclast progenitors. An imbalance of osteoclast and osteoblast activity results in certain diseases including osteoporosis.Receptor activator of NF-kB ligand (RANKL), also known as osteoclast differentiation factor (ODF) and osteoprotegerin ligand (OPGL), belonging to a member of the tumor necrosis factor (TNF) ligand family, is expressed on osteoblasts/stromal cells as a type-2 membrane protein in response to the stimulators of bone resorption (2-4). RANKL induces osteoclastogenesis by sending signals to osteoclast progenitors. RANKL was first cloned as a regulatory factor of dendritic cells (5) and is also identical to TNF-related activation-induced cytokine (TRANCE), which was cloned as a regulatory factors of T cells (6). RANK, a member of the TNF receptor (TNFR) family, was identified as a receptor for RANKL. The interaction between RANKL expressed by osteoblasts/stromal cells and RANK expressed on osteoclast precursors is essential for osteoclastogenesis (7). Osteoprotegerin (OPG) (8), also known as osteoclastogenesis inhibitory factor (OCIF) (9 -11), is a secreted member of the TNFR family. OPG is a decoy receptor of RANKL and inhibits osteoclast maturation. RANKL, RANK, and OPG play critical roles in bone metabolism.To date the three-dimensional structures of four ligands belonging to the TNF family have been...

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The aim of this study is to elucidate the usefulness of plasma D-dimer for the prediction of thrombotic events in highly atherosclerotic patients. The severity of atherosclerosis was measured by non-invasive methods including cardio-ankle vascular index (CAVI) and carotid intima-media thickness (IMT) in 100 patients with atherosclerosis aged 72.1 years on average. CAVI was significantly correlated with the levels of D-dimer, platelet aggregation (Plt Aggre), uric acid (UA), creatinine (Cr), blood urea nitrogen (BUN), and C-reactive protein (CRP), whereas IMT was significantly correlated with the levels of Cr, BUN, and CRP. CAVI and IMT were suitable for stratification of the patients. A comparison of hemostatic markers (D-dimer, fibrinogen and Plt Aggre) between the less sclerotic group (group A; CAVI <8.0 and IMT <1.1 mm, n = 26) and the highly sclerotic group (group B; CAVI >8.0 and IMT >1.1 mm, n = 32) revealed that the incidence of thrombosis was significantly higher in group B (18.8%) than in group A (3.8%) and that D-dimer was significantly higher (p < 0.01, Mann-Whitney U test) in group B (0.48 mug/ml, median) than in group A (0.32 mug/ml, median). Moreover, multiple linear regression analyses of CAVI and IMT indicated that D-dimer and age were significant variables. In conclusion, D-dimer is significantly associated with thrombosis in highly atherosclerotic patients.

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